Is GOT2 p.Val76Ile (c.226G>A) pathogenic?

GOT2 p.Val76Ile (c.226G>A) is classified Uncertain significance in GOT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-03). AlphaMissense: likely benign (0.1076); Rare (popmax 0.163%, afr).

How common is GOT2 p.Val76Ile (c.226G>A) in the general population?

GOT2 p.Val76Ile (c.226G>A) is rare (popmax 0.163%, afr) (gnomAD).

What do computational predictors say about GOT2 p.Val76Ile (c.226G>A)?

AlphaMissense predicts likely benign (score 0.1076) — an in-silico prediction, not a clinical call.

GOT2 p.Val76Ile

c.226G>A · rs144716246 · VCV1436360

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1076 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.163%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1076	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -8.56	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 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 26 kb · p 4.2e-08 · regional, not allelic
Overall
CADD	22.5	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.163% African / African-American · 122/74,994 alleles

Filtering AF 0.139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.13%

Overall 0.0156% 252/1,613,018 alleles · rare exomes 170/1,460,766 · genomes 82/152,252 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.163%	615
South Asian	0.0868%	1,153
East Asian	0.0156%	6,409
Admixed American	0.0117%	8,571
Remaining individualsnot grpmax-eligible	0.0112%	8,925
European (non-Finnish)	0.00254%	39,302

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: GOT2
Protein: p.Val76Ile
Coding: c.226G>A
MANE Select: NM_002080
dbSNP: rs144716246
Type: single nucleotide variant
Location: chr16:58723766 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI 0.49 (gnomAD)
Structure: AlphaFold pLDDT 94.77 · 3 PDB

Full GOT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GOT2 p.Val76= Benign ★★ same residue
GOT2 p.Arg262Gly Likely pathogenic ★★ same type
GOT2 p.Gly366Val Likely pathogenic ★★ same type
GOT2 p.Ala89Ser Uncertain significance ★★ ⚠ same type
GOT2 p.Arg325Gln Uncertain significance ★★ ⚠ same type
GOT2 p.Asp190Val Uncertain significance ★★ ⚠ same type
GOT2 p.Asp197Asn Uncertain significance ★★ ⚠ same type
GOT2 p.Gln357Glu Uncertain significance ★★ ⚠ 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/got2-p-val76ile (accessed [today's date]).

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