SLC4A1

Chr 17ADAR

solute carrier family 4 member 1 (Diego blood group)

Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein (PubMed:10926824, PubMed:14734552, PubMed:1538405, PubMed:16227998, PubMed:20151848, PubMed:24121512, PubMed:28387307, PubMed:35835865). Component of the ankyrin-1 complex of the erythrocyte membrane; required for normal flexibility and stability of the erythrocyte membrane and for normal erythrocyte shape via the interactions of its cytoplasmic domain with cytoskeletal proteins, glycolytic enzymes, and hemoglobin (PubMed:1538405, PubMed:20151848, PubMed:35835865). Functions as a transporter that mediates the 1:1 exchange of inorganic anions across the erythrocyte membrane. Mediates chloride-bicarbonate exchange in the kidney, and is required for normal acidification of the urine (PubMed:10926824, PubMed:14734552, PubMed:16227998, PubMed:24121512, PubMed:28387307)

Primary Disease Associations & Inheritance

[Blood group, Diego]MIM #110500

[Blood group, Froese]MIM #601551

[Blood group, Swann]MIM #601550

[Blood group, Waldner]MIM #112010

[Blood group, Wright]MIM #112050

{Malaria, resistance to}MIM #611162

CryohydrocytosisMIM #185020

Distal renal tubular acidosis 1MIM #179800

Distal renal tubular acidosis 4 with hemolytic anemiaMIM #611590

Ovalocytosis, SA typeMIM #166900

Spherocytosis, type 4MIM #612653

UniProtOvalocytosis, Southeast Asian

UniProtSpherocytosis 4

ClinVar variants

Pathogenic / LP

0.85

pLI score

Active trials

Clinical Summary— SLC4A1

⚡

Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.85) — some intolerance to loss-of-function variants.

Some data sources returned errors (2)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

clinvarCount: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

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.

0.35LOEUF

pLI 0.846

Z-score 4.81

OE 0.19 (0.11–0.35)

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.

1.66Z-score

OE missense 0.80 (0.74–0.86)

426 obs / 534.0 exp

Tolerant

Mild missense constraint

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.0.19 (0.11–0.35)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.80 (0.74–0.86)

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.1.05

0≤1.21.6

LoF obs/exp: 8 / 41.4Missense obs/exp: 426 / 534.0Syn Z: -0.58