Is USH2A p.Met1Val (c.1A>G) pathogenic?

USH2A p.Met1Val (c.1A>G) is classified Conflicting classifications of pathogenicity in USH2A (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2024-01-18). Ultra-rare (popmax 0.0174%, afr); Associated with USH2A-related disorder.

What condition is associated with USH2A p.Met1Val (c.1A>G)?

USH2A p.Met1Val (c.1A>G) is associated with USH2A-related disorder, Usher syndrome type 2A, retinitis pigmentosa 39 (ClinVar).

How common is USH2A p.Met1Val (c.1A>G) in the general population?

USH2A p.Met1Val (c.1A>G) is ultra-rare (popmax 0.0174%, afr) (gnomAD).

USH2A p.Met1Val

c.1A>G · rs924627806 · VCV553979

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, afr)

Conditions

USH2A-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.349	indeterminate
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5	GERP 1.8, phastCons 1
Overall
CADD	18.92	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0174% African / African-American · 13/74,892 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.000868% 14/1,613,566 alleles · ultra-rare exomes 6/1,461,442 · genomes 8/152,124 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0174%	5,761
East Asian	0.00223%	44,856

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.Met1Val
Coding: c.1A>G
MANE Select: NM_206933
dbSNP: rs924627806
Type: single nucleotide variant
Location: chr1:216422336 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

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

Disease context

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

Similar variants

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
USH2A p.Asn4292Asp Likely 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-met1val (accessed [today's date]).

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