Is WHRN p.Pro664= (c.1992G>A) pathogenic?

WHRN p.Pro664= (c.1992G>A) is classified Conflicting classifications of pathogenicity in WHRN (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-24). Rare (popmax 0.276%, afr); Associated with Usher syndrome type 2D.

What condition is associated with WHRN p.Pro664= (c.1992G>A)?

WHRN p.Pro664= (c.1992G>A) is associated with Usher syndrome type 2D, autosomal recessive nonsyndromic hearing loss 31 (ClinVar).

How common is WHRN p.Pro664= (c.1992G>A) in the general population?

WHRN p.Pro664= (c.1992G>A) is rare (popmax 0.276%, afr) (gnomAD).

WHRN p.Pro664=

c.1992G>A · rs142568702 · VCV178336

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.276%, 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20	GERP -4
Overall
CADD	0.014	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.276% African / African-American · 207/74,920 alleles

Filtering AF 0.245% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.234%

Overall 0.0214% 344/1,610,300 alleles · rare exomes 221/1,458,092 · genomes 123/152,208 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.276%	362
Middle Eastern	0.0331%	3,018
Remaining individualsnot grpmax-eligible	0.0257%	3,897
European (non-Finnish)	0.00909%	11,003
South Asian	0.0088%	11,367
Admixed American	0.00667%	14,983

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.Pro664=
Coding: c.1992G>A
MANE Select: NM_015404
dbSNP: rs142568702
Type: single nucleotide variant
Location: chr9:114406599 (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.Pro664Leu 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
WHRN p.Ala885Thr Uncertain significance ★★ ⚠ same condition
WHRN p.Arg366His Uncertain significance ★★ ⚠ same condition
WHRN p.Arg490His 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-pro664 (accessed [today's date]).

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