Is WHRN p.Ala409= (c.1227C>T) pathogenic?

WHRN p.Ala409= (c.1227C>T) is classified Conflicting classifications of pathogenicity in WHRN (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-04-01). Ultra-rare (popmax 0.066%, mid); Associated with Usher syndrome type 2D.

What condition is associated with WHRN p.Ala409= (c.1227C>T)?

WHRN p.Ala409= (c.1227C>T) is associated with Usher syndrome type 2D, autosomal recessive nonsyndromic hearing loss 31 (ClinVar).

How common is WHRN p.Ala409= (c.1227C>T) in the general population?

WHRN p.Ala409= (c.1227C>T) is ultra-rare (popmax 0.066%, mid) (gnomAD).

WHRN p.Ala409=

c.1227C>T · rs758129253 · VCV364692

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Conditions

Usher syndrome type 2D

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 -9.9	GERP -4.8
Overall
CADD	0.718	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.066% Middle Eastern · 4/6,064 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00502% 81/1,613,126 alleles · ultra-rare exomes 77/1,460,952 · genomes 4/152,174 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.00962%	10,400
East Asian	0.00669%	14,950
European (non-Finnish)	0.00543%	18,432
African / African-American	0.00534%	18,726

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.Ala409=
Coding: c.1227C>T
MANE Select: NM_015404
dbSNP: rs758129253
Type: single nucleotide variant
Location: chr9:114424523 (GRCh38)
Gene constraint: LOEUF 0.808 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 59.39 · 5 PDB

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

Disease context

Usher syndrome type 2D — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 31

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-ala409 (accessed [today's date]).

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