Is SAG p.Val403Ala (c.1208T>C) pathogenic?

SAG p.Val403Ala (c.1208T>C) is classified Benign in SAG (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0529); Common (popmax 23.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with inherited retinal dystrophy.

What condition is associated with SAG p.Val403Ala (c.1208T>C)?

SAG p.Val403Ala (c.1208T>C) is associated with inherited retinal dystrophy, Oguchi disease, retinitis pigmentosa (ClinVar).

What do computational predictors say about SAG p.Val403Ala (c.1208T>C)?

AlphaMissense predicts likely benign (score 0.0529) — an in-silico prediction, not a clinical call.

SAG p.Val403Ala

Q: How common is SAG p.Val403Ala (c.1208T>C) in the general population?

SAG p.Val403Ala (c.1208T>C) is common (popmax 23.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1208T>C · rs1046976 · VCV335074

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0529 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 23.8%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.0529	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -5.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.79
Overall
CADD	0.116	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 23.8% African / African-American · 17,790/74,714 alleles

Filtering AF 23.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 23.4%

Overall 9.09% 145,067/1,596,666 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	23.8%	4
South Asian	12.6%	8
Amishnot grpmax-eligible	10.9%	9
Remaining individualsnot grpmax-eligible	9.49%	11
Finnishnot grpmax-eligible	8.77%	11
European (non-Finnish)	8.12%	12
Admixed American	7.92%	13
Ashkenazi Jewishnot grpmax-eligible	7.73%	13
Middle Eastern	6.61%	15
East Asian	5.02%	20

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: SAG
Protein: p.Val403Ala
Coding: c.1208T>C
MANE Select: NM_014245 · reported on NM_000541
dbSNP: rs1046976
Type: single nucleotide variant
Location: chr2:233346902 (GRCh38)
Structure: AlphaFold pLDDT 83.02 · 7 PDB

Full SAG 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: Oguchi disease retinitis pigmentosa

Similar variants

SAG p.Val403Ile Benign ★★ same residue
SAG c.1103-2A>C Pathogenic/Likely pathogenic ★★ same condition
SAG c.136+2T>G Pathogenic/Likely pathogenic ★★ same condition
SAG p.Arg193Ter Pathogenic ★★ same condition
SAG p.Arg292Ter Pathogenic ★★ same condition
SAG p.Gln191Ter Pathogenic/Likely pathogenic ★★ same condition
SAG c.944+5G>A Uncertain significance ★★ same condition
SAG p.Ala100Thr Uncertain significance ★★ ⚠ 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/sag-p-val403ala (accessed [today's date]).

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