Is WHRN p.Leu320Phe (c.958C>T) pathogenic?

WHRN p.Leu320Phe (c.958C>T) is classified Uncertain significance in WHRN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2023-08-01). AlphaMissense: likely pathogenic (0.5704); Very rare (popmax 0.00593%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 31.

What condition is associated with WHRN p.Leu320Phe (c.958C>T)?

WHRN p.Leu320Phe (c.958C>T) is associated with autosomal recessive nonsyndromic hearing loss 31, Usher syndrome type 2D (ClinVar).

How common is WHRN p.Leu320Phe (c.958C>T) in the general population?

WHRN p.Leu320Phe (c.958C>T) is very rare (popmax 0.00593%, nfe) (gnomAD).

What do computational predictors say about WHRN p.Leu320Phe (c.958C>T)?

AlphaMissense predicts likely pathogenic (score 0.5704) — an in-silico prediction, not a clinical call.

WHRN p.Leu320Phe

c.958C>T · rs780855079 · VCV811003

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.5704 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00593%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal recessive nonsyndromic hearing loss 31

Computational evidence

Protein change
AlphaMissense	0.5704	likely pathogenic
REVEL	0.389	indeterminate
SaProt	LLR -11.07	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 102 kb · p 0.96 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00593% European (non-Finnish) · 70/1,180,034 alleles

Filtering AF 0.00478% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00439%

Overall 0.00465% 75/1,613,862 alleles · very rare exomes 68/1,461,642 · genomes 7/152,220 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00593%	16,858
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Admixed American	0.00333%	30,007

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: WHRN
Protein: p.Leu320Phe
Coding: c.958C>T
MANE Select: NM_015404
dbSNP: rs780855079
Type: single nucleotide variant
Location: chr9:114466272 (GRCh38)
Gene constraint: LOEUF 0.808 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 59.39 · 5 PDB
Residue 320: the pdz 2 domain

Full WHRN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive nonsyndromic hearing loss 31 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 2D

Similar variants

WHRN c.1417-1G>A Pathogenic/Likely pathogenic ★★ same condition
WHRN p.Arg778Ter Pathogenic ★★ same condition
WHRN c.*156G>A Uncertain significance ★★ same condition
WHRN p.Ala631Val Uncertain significance ★★ ⚠ same condition
WHRN p.Ala885Thr Uncertain significance ★★ ⚠ same condition
WHRN p.Arg366His Uncertain significance ★★ ⚠ same condition
WHRN p.Arg490His Uncertain significance ★★ ⚠ same condition
WHRN p.Arg745His Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/whrn-p-leu320phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown