Is USH2A p.Arg449His (c.1346G>A) pathogenic?

USH2A p.Arg449His (c.1346G>A) is classified Conflicting classifications of pathogenicity in USH2A (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.0662); Rare (popmax 0.228%, eas); Associated with inherited retinal dystrophy.

What condition is associated with USH2A p.Arg449His (c.1346G>A)?

USH2A p.Arg449His (c.1346G>A) is associated with inherited retinal dystrophy, Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Arg449His (c.1346G>A) in the general population?

USH2A p.Arg449His (c.1346G>A) is rare (popmax 0.228%, eas) (gnomAD).

What do computational predictors say about USH2A p.Arg449His (c.1346G>A)?

AlphaMissense predicts likely benign (score 0.0662) — an in-silico prediction, not a clinical call.

USH2A p.Arg449His

c.1346G>A · rs766715882 · VCV631593

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0662 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.228%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.0662	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -5.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3.9	GERP -3.3
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	14.25	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 0.228% East Asian · 102/44,790 alleles

Filtering AF 0.192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.178%

Overall 0.00936% 151/1,613,182 alleles · rare exomes 145/1,461,218 · genomes 6/151,964 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.228%	439
Admixed American	0.00834%	11,986
South Asian	0.00549%	18,213
African / African-American	0.00535%	18,699
Remaining individualsnot grpmax-eligible	0.0032%	31,222
European (non-Finnish)	0.0028%	35,746

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.Arg449His
Coding: c.1346G>A
MANE Select: NM_206933
dbSNP: rs766715882
Type: single nucleotide variant
Location: chr1:216323678 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 449: the laminin n-terminal 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.Arg449Cys Uncertain significance ★★ ⚠ same residue
USH2A p.Arg449Leu Uncertain significance ★ ⚠ same residue
USH2A p.Arg449= 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

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-arg449his (accessed [today's date]).

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