Is USH2A p.Ser1349Phe (c.4046C>T) pathogenic?

USH2A p.Ser1349Phe (c.4046C>T) is classified Uncertain significance in USH2A (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-06-03). AlphaMissense: likely benign (0.1133); Ultra-rare (popmax 0.032%, afr); Associated with retinitis pigmentosa 39.

What condition is associated with USH2A p.Ser1349Phe (c.4046C>T)?

USH2A p.Ser1349Phe (c.4046C>T) is associated with retinitis pigmentosa 39, Usher syndrome type 2A (ClinVar).

How common is USH2A p.Ser1349Phe (c.4046C>T) in the general population?

USH2A p.Ser1349Phe (c.4046C>T) is ultra-rare (popmax 0.032%, afr) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about USH2A p.Ser1349Phe (c.4046C>T)?

AlphaMissense predicts likely benign (score 0.1133) — an in-silico prediction, not a clinical call.

USH2A p.Ser1349Phe

c.4046C>T · rs145148501 · VCV1215648

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1133 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.032%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

retinitis pigmentosa 39

Computational evidence

Protein change
AlphaMissense	0.1133	likely benign
REVEL	0.153	moderately 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 4.4	GERP -0.28, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 797 kb · p 0.00011 · regional, not allelic
Overall
CADD	17.39	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 0.032% African / African-American · 24/75,036 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.00235% 38/1,613,994 alleles · ultra-rare exomes 22/1,461,736 · genomes 16/152,258 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.032%	3,127
Admixed American	0.00167%	60,022
European (non-Finnish)	0.0011%	90,766

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.Ser1349Phe
Coding: c.4046C>T
MANE Select: NM_206933
dbSNP: rs145148501
Type: single nucleotide variant
Location: chr1:216198350 (GRCh38)
Gene constraint: LOEUF 0.855 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1349: the fibronectin type-iii 3 domain; a UniProt-annotated variant site (in)

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

Disease context

retinitis pigmentosa 39 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Usher syndrome type 2A

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

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-ser1349phe (accessed [today's date]).

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