Is WHRN p.Arg682= (c.2046G>C) pathogenic?

WHRN p.Arg682= (c.2046G>C) is classified Conflicting classifications of pathogenicity in WHRN (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-01). Low-frequency (popmax 1.78%, afr); Associated with Usher syndrome type 2D.

What condition is associated with WHRN p.Arg682= (c.2046G>C)?

WHRN p.Arg682= (c.2046G>C) is associated with Usher syndrome type 2D, autosomal recessive nonsyndromic hearing loss 31 (ClinVar).

How common is WHRN p.Arg682= (c.2046G>C) in the general population?

WHRN p.Arg682= (c.2046G>C) is low-frequency (popmax 1.78%, afr) (gnomAD).

WHRN p.Arg682=

c.2046G>C · rs35258467 · VCV45665

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.78%, afr)

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 -0.33	GERP -4, phastCons 0.14
Overall
CADD	4.719	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.78% African / African-American · 1,336/75,002 alleles

Filtering AF 1.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.67%

Overall 0.0977% 1,576/1,612,892 alleles · low-frequency exomes 801/1,460,640 · genomes 775/152,252 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.78%	56
Admixed American	0.143%	697
Remaining individualsnot grpmax-eligible	0.13%	771
Middle Eastern	0.033%	3,029
South Asian	0.00659%	15,171
European (non-Finnish)	0.00551%	18,142

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.Arg682=
Coding: c.2046G>C
MANE Select: NM_015404
dbSNP: rs35258467
Type: single nucleotide variant
Location: chr9:114406545 (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 p.Arg682Leu Uncertain significance ★★ ⚠ same residue
WHRN p.Arg682Trp Uncertain significance ★★ ⚠ same residue
WHRN p.Arg682Gln Uncertain significance ★ ⚠ same residue
WHRN p.Arg682Pro Uncertain significance ★ ⚠ same residue
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

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-arg682 (accessed [today's date]).

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