Is GOT2 p.Arg53Trp (c.157A>T) pathogenic?

GOT2 p.Arg53Trp (c.157A>T) is classified Uncertain significance in GOT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-29). AlphaMissense: ambiguous (0.4232); Ultra-rare (popmax 0.0118%, nfe).

How common is GOT2 p.Arg53Trp (c.157A>T) in the general population?

GOT2 p.Arg53Trp (c.157A>T) is ultra-rare (popmax 0.0118%, nfe) (gnomAD).

What do computational predictors say about GOT2 p.Arg53Trp (c.157A>T)?

AlphaMissense predicts ambiguous (score 0.4232) — an in-silico prediction, not a clinical call.

GOT2 p.Arg53Trp

c.157A>T · VCV4030964

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4232 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4232	ambiguous
REVEL	0.251	benign-leaning
SaProt	LLR -14.88	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 26 kb · p 4.2e-08 · regional, not allelic
Overall
CADD	26.6	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 0.0118% European (non-Finnish) · 139/1,179,292 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00956%

Overall 0.00917% 148/1,613,212 alleles · ultra-rare exomes 142/1,461,018 · genomes 6/152,194 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0118%	8,484
Remaining individualsnot grpmax-eligible	0.00961%	10,406
Finnishnot grpmax-eligible	0.00312%	32,022
African / African-American	0.00133%	74,912

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.Arg53Trp
Coding: c.157A>T
MANE Select: NM_002080
Type: single nucleotide variant
Location: chr16:58723835 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI 0.49 (gnomAD)
Structure: AlphaFold pLDDT 94.77 · 3 PDB
Residue 53: an α-helix

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

Similar variants

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
GOT2 p.Gln372Arg 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-arg53trp (accessed [today's date]).

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