Is USH2A p.Arg2001His (c.6002G>A) pathogenic?

USH2A p.Arg2001His (c.6002G>A) is classified Uncertain significance in USH2A (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-04). AlphaMissense: likely benign (0.0685); Very rare (popmax 0.00333%, amr).

How common is USH2A p.Arg2001His (c.6002G>A) in the general population?

USH2A p.Arg2001His (c.6002G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about USH2A p.Arg2001His (c.6002G>A)?

AlphaMissense predicts likely benign (score 0.0685) — an in-silico prediction, not a clinical call.

USH2A p.Arg2001His

c.6002G>A · rs759963430 · VCV2179680

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0685	likely benign
REVEL	0.002	strongly benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -3.9
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	0.525	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,982 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00149% 24/1,613,836 alleles · very rare exomes 23/1,461,724 · genomes 1/152,112 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,823
Admixed Americangrpmax	0.00333%	29,991
European (non-Finnish)	0.00153%	65,552
South Asian	0.0011%	91,092

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg2001His
Coding: c.6002G>A
MANE Select: NM_206933
dbSNP: rs759963430
Type: single nucleotide variant
Location: chr1:216070148 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2001: the fibronectin type-iii 6 domain

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

Similar variants

USH2A p.Arg2001Cys Benign/Likely benign ★★ same residue
USH2A p.Arg2001Gly Uncertain significance ★ ⚠ same residue
USH2A c.12295-3T>A Pathogenic ★★★ same type
USH2A c.8559-2A>G Pathogenic ★★★ same type
USH2A c.8682-9A>G Pathogenic ★★★ same type
USH2A p.Ala4740Asp Pathogenic ★★★ ⚠ same type
USH2A p.Arg3905Cys Pathogenic ★★★ ⚠ same type
USH2A p.Arg4192Cys Likely pathogenic ★★★ ⚠ same type

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-arg2001his (accessed [today's date]).

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