Is USH2A p.Asp644Val (c.1931A>T) pathogenic?

USH2A p.Asp644Val (c.1931A>T) is classified Benign/Likely benign in USH2A (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-04-02). AlphaMissense: likely benign (0.1709); Common (popmax 14.5%, mid) — too common for a highly-penetrant pathogenic allele; Associated with inherited retinal dystrophy.

What condition is associated with USH2A p.Asp644Val (c.1931A>T)?

USH2A p.Asp644Val (c.1931A>T) is associated with inherited retinal dystrophy, Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

What do computational predictors say about USH2A p.Asp644Val (c.1931A>T)?

AlphaMissense predicts likely benign (score 0.1709) — an in-silico prediction, not a clinical call.

USH2A p.Asp644Val

Q: How common is USH2A p.Asp644Val (c.1931A>T) in the general population?

USH2A p.Asp644Val (c.1931A>T) is common (popmax 14.5%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1931A>T · rs1805048 · VCV48478

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.1709 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 14.5%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.1709	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -9.15	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.5	GERP 1.8, phastCons 0.7
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	19.7	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 14.5% Middle Eastern · 876/6,062 alleles

Filtering AF 13.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 13.3%

Overall 6.65% 107,281/1,613,914 alleles · common exomes 99,598/1,461,660 · genomes 7,683/152,254 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	14.5%	7
Ashkenazi Jewishnot grpmax-eligible	13%	8
Amishnot grpmax-eligible	7.68%	13
European (non-Finnish)	7.37%	14
Remaining individualsnot grpmax-eligible	7.23%	14
South Asian	5.86%	17
Admixed American	4.3%	23
Finnishnot grpmax-eligible	3.18%	31
African / African-American	1.36%	73
East Asian	0.0557%	1,794

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: USH2A
Protein: p.Asp644Val
Coding: c.1931A>T
MANE Select: NM_206933
dbSNP: rs1805048
Type: single nucleotide variant
Location: chr1:216289320 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 644: a UniProt-annotated variant site (in); the laminin egf-like 3 domain

Full USH2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 2A retinitis pigmentosa 39 retinitis pigmentosa

Similar variants

USH2A p.Asp644= Likely benign ★ same residue
USH2A c.12295-3T>A Pathogenic ★★★ same condition
USH2A c.8559-2A>G Pathogenic ★★★ same condition
USH2A c.8682-9A>G Pathogenic ★★★ same condition
USH2A p.Ala4740Asp Pathogenic ★★★ ⚠ same condition
USH2A p.Arg3905Cys Pathogenic ★★★ ⚠ same condition
USH2A p.Arg4192Cys Likely pathogenic ★★★ ⚠ same condition
USH2A p.Asn346His Pathogenic ★★★ 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/ush2a-p-asp644val (accessed [today's date]).

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