Is WHRN p.Ser774= (c.2322C>T) pathogenic?

WHRN p.Ser774= (c.2322C>T) is classified Conflicting classifications of pathogenicity in WHRN (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-13). Rare (popmax 0.122%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 31.

What condition is associated with WHRN p.Ser774= (c.2322C>T)?

WHRN p.Ser774= (c.2322C>T) is associated with autosomal recessive nonsyndromic hearing loss 31, Usher syndrome type 2D (ClinVar).

How common is WHRN p.Ser774= (c.2322C>T) in the general population?

WHRN p.Ser774= (c.2322C>T) is rare (popmax 0.122%, nfe) (gnomAD).

WHRN p.Ser774=

c.2322C>T · rs55966714 · VCV227292

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.122%, nfe)

Conditions

autosomal recessive nonsyndromic hearing loss 31

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.7	GERP -4
Overall
CADD	0.752	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.122% European (non-Finnish) · 1,439/1,180,028 alleles

Filtering AF 0.117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.115%

Overall 0.0963% 1,553/1,612,590 alleles · rare exomes 1,460/1,460,268 · genomes 93/152,322 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.122%	820
Remaining individualsnot grpmax-eligible	0.0944%	1,059
Admixed American	0.0633%	1,580
Middle Eastern	0.033%	3,031
Finnishnot grpmax-eligible	0.0112%	8,920
African / African-American	0.00799%	12,510
South Asian	0.0022%	45,537

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.Ser774=
Coding: c.2322C>T
MANE Select: NM_015404
dbSNP: rs55966714
Type: single nucleotide variant
Location: chr9:114403992 (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 774: the 'disordered' region

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-ser774 (accessed [today's date]).

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