Is WHRN p.Pro676Arg (c.2027C>G) pathogenic?

WHRN p.Pro676Arg (c.2027C>G) is classified Conflicting classifications of pathogenicity in WHRN (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.1059); Rare (popmax 0.12%, nfe); Associated with Usher syndrome type 2D.

What condition is associated with WHRN p.Pro676Arg (c.2027C>G)?

WHRN p.Pro676Arg (c.2027C>G) is associated with Usher syndrome type 2D, hearing loss disorder, autosomal recessive nonsyndromic hearing loss 31 (ClinVar).

How common is WHRN p.Pro676Arg (c.2027C>G) in the general population?

WHRN p.Pro676Arg (c.2027C>G) is rare (popmax 0.12%, nfe) (gnomAD).

What do computational predictors say about WHRN p.Pro676Arg (c.2027C>G)?

AlphaMissense predicts likely benign (score 0.1059) — an in-silico prediction, not a clinical call.

WHRN p.Pro676Arg

c.2027C>G · rs139279977 · VCV203387

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.1059 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.12%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Usher syndrome type 2D

Computational evidence

Protein change
AlphaMissense	0.1059	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 102 kb · p 0.96 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.12% European (non-Finnish) · 1,415/1,178,344 alleles

Filtering AF 0.115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.113%

Overall 0.096% 1,547/1,611,568 alleles · rare exomes 1,450/1,459,350 · genomes 97/152,218 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.12%	833
Finnishnot grpmax-eligible	0.0974%	1,027
Remaining individualsnot grpmax-eligible	0.077%	1,299
African / African-American	0.0227%	4,404
Admixed American	0.00667%	14,983
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,524

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.Pro676Arg
Coding: c.2027C>G
MANE Select: NM_015404
dbSNP: rs139279977
Type: single nucleotide variant
Location: chr9:114406564 (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: hearing loss disorder 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-pro676arg (accessed [today's date]).

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