Is AGXT p.Val376Met (c.1126G>A) pathogenic?

AGXT p.Val376Met (c.1126G>A) is classified Uncertain significance in AGXT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-15). AlphaMissense: likely benign (0.2742); Ultra-rare (popmax 0.0226%, eas); Associated with Inborn genetic diseases.

What condition is associated with AGXT p.Val376Met (c.1126G>A)?

AGXT p.Val376Met (c.1126G>A) is associated with Inborn genetic diseases (ClinVar).

How common is AGXT p.Val376Met (c.1126G>A) in the general population?

AGXT p.Val376Met (c.1126G>A) is ultra-rare (popmax 0.0226%, eas) (gnomAD).

What do computational predictors say about AGXT p.Val376Met (c.1126G>A)?

AlphaMissense predicts likely benign (score 0.2742) — an in-silico prediction, not a clinical call.

AGXT p.Val376Met

c.1126G>A · rs759836341 · VCV2523265

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2742 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0226%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2742	likely benign
REVEL	0.464	indeterminate
SaProt	LLR -10.05	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.29	GERP -2.5, phastCons 0.006
Regional constraint	o/e 1.00	unconstrained · MANE · 9,952 bp · p 0.92 · regional, not allelic
Overall
CADD	18.77	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 0.0226% East Asian · 10/44,162 alleles

Filtering AF 0.0122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0093%

Overall 0.00251% 40/1,593,936 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0226%	4,416
Remaining individualsnot grpmax-eligible	0.0097%	10,314
African / African-American	0.00401%	24,931
Admixed American	0.0035%	28,589
South Asian	0.00228%	43,773
European (non-Finnish)	0.00145%	69,041

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: AGXT
Protein: p.Val376Met
Coding: c.1126G>A
MANE Select: NM_000030
dbSNP: rs759836341
Type: single nucleotide variant
Location: chr2:240878768 (GRCh38)
Gene constraint: LOEUF 1.251 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 98.30 · 17 PDB
Residue 376: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AGXT p.Val376= Likely benign ★ same residue
AGXT p.Val376Leu Uncertain significance ⚠ same residue
AGXT p.Ser81Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
AGXT c.847-3C>T Uncertain significance ★★ same condition
AGXT p.Ala296Val Uncertain significance ★★ ⚠ same condition
AGXT p.Ala382Val Uncertain significance ★★ ⚠ same condition
AGXT p.Val266Ile Uncertain significance ★★ ⚠ same condition
AGXT p.Ala13Pro 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/agxt-p-val376met (accessed [today's date]).

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