SLC4A2

Chr 7

solute carrier family 4 member 2

Also known as: AE2, BND3L, EPB3L1, HKB3, NBND3, OPTB9

NCBI Gene: 6522ENSG00000164889UniProt: P04920

This gene encodes a member of the anion exchanger family of membrane transport proteins. The encoded protein regulates intracellular pH, biliary bicarbonate secretion, and chloride uptake. Reduced expression of this gene may be associated with primary biliary cirrhosis (PBC) in human patients, while differential expression of this gene may be associated with malignant hepatocellular carcinoma, colon and gastric cancers. [provided by RefSeq, Nov 2016]

Primary Disease Associations & Inheritance

UniProtOsteopetrosis, autosomal recessive 9
261
ClinVar variants
76
Pathogenic / LP
0.99
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SLC4A2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
76 Pathogenic / Likely Pathogenic· 174 VUS of 261 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.30LOEUF
pLI 0.985
Z-score 5.56
OE 0.17 (0.10–0.30)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.97Z-score
OE missense 0.71 (0.66–0.76)
566 obs / 802.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.17 (0.10–0.30)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.71 (0.66–0.76)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.96
0≤1.21.6
LoF obs/exp: 9 / 52.5Missense obs/exp: 566 / 802.7Syn Z: 0.54

ClinVar Variant Classifications

261 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic71
Likely Pathogenic5
VUS174
Likely Benign9
Benign2
71
Pathogenic
5
Likely Pathogenic
174
VUS
9
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
69
0
71
Likely Pathogenic
0
1
4
0
5
VUS
0
161
8
5
174
Likely Benign
0
3
3
3
9
Benign
0
0
0
2
2
Total01678410261

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SLC4A2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

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GeneReview available — SLC4A2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
SLC4A2, another gene involved in acid-base balancing machinery of osteoclasts, causes osteopetrosis.
Xue JY et al.·Bone
2023Review
SLC4A2 Deficiency Causes a New Type of Osteopetrosis.
Xue JY et al.·J Bone Miner Res
2022Case report
Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid-Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario.
Calvete O et al.·Cells
2021Functional
Common genetic variation and haplotypes of the anion exchanger SLC4A2 in primary biliary cirrhosis.
Juran BD et al.·Am J Gastroenterol
2009
A deletion mutation in bovine SLC4A2 is associated with osteopetrosis in Red Angus cattle.
Meyers SN et al.·BMC Genomics
2010
Clinical characteristics and genetic profiles of young and adult patients with cholestatic liver disease.
Huynh MT et al.·Rev Esp Enferm Dig
2019Cohort
Molecular physiology of SLC4 anion exchangers.
Alper SL·Exp Physiol
2006Review
Genetic factors of susceptibility and of severity in primary biliary cirrhosis.
Poupon R et al.·J Hepatol
2008
Ductal variant prostate carcinoma is associated with a significantly shorter metastasis-free survival.
Chow K et al.·Eur J Cancer
2021
SLC4A2 anion exchanger promotes tumour cell malignancy via enhancing net acid efflux across golgi membranes.
Khosrowabadi E et al.·Cell Mol Life Sci
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools