NHERF2

Chr 16AD

NHERF family PDZ scaffold protein 2

Also known as: E3KARP, NHE3RF2, NHERF-2, OCTS2, SIP-1, SIP1, SLC9A3R2, TKA-1

NCBI Gene: 9351ENSG00000065054UniProt: Q15599OMIM: 606553

This gene encodes a PDZ scaffolding protein that connects plasma membrane proteins to the actin cytoskeleton and regulates their surface expression, including the sodium/hydrogen exchanger 3 and the cystic fibrosis transmembrane regulator ion channel. Mutations cause autosomal dominant deafness (DFNA82). The gene shows tolerance to loss-of-function variants with a low pLI score.

OMIMResearchSummary from RefSeq, OMIM, UniProt
MultiplemechanismADLOEUF 0.701 OMIM phenotype
Clinical Summary— NHERF2
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.
📋
ClinVar Variants
45 unique Pathogenic / Likely Pathogenic· 106 VUS of 165 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.70LOEUF
pLI 0.038
Z-score 2.39
OE 0.33 (0.17–0.70)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
-0.17Z-score
OE missense 1.03 (0.92–1.16)
209 obs / 202.1 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.33 (0.17–0.70)
0≤0.351.4
Missense OE1.03 (0.92–1.16)
0≤0.61.4
Synonymous OE1.13
0≤1.21.6
LoF obs/exp: 5 / 15.0Missense obs/exp: 209 / 202.1Syn Z: -0.95
DN
0.6841th %ile
GOF
0.81top 10%
LOF
0.3259th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

165 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic44
Likely Pathogenic1
VUS106
Likely Benign6
Benign2
44
Pathogenic
1
Likely Pathogenic
106
VUS
6
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
44
0
44
Likely Pathogenic
0
0
1
0
1
VUS
0
88
16
2
106
Likely Benign
0
4
1
1
6
Benign
0
2
0
0
2
Total094623159

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

View in ClinVar →

Protein Context — Lollipop Plot

NHERF2 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 4 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients