Is GOT2 p.Pro221Leu (c.662C>T) pathogenic?

GOT2 p.Pro221Leu (c.662C>T) is classified Uncertain significance in GOT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-18). AlphaMissense: likely pathogenic (0.7222); Absent from gnomAD v4.1.

How common is GOT2 p.Pro221Leu (c.662C>T) in the general population?

GOT2 p.Pro221Leu (c.662C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GOT2 p.Pro221Leu (c.662C>T)?

AlphaMissense predicts likely pathogenic (score 0.7222) — an in-silico prediction, not a clinical call.

GOT2 p.Pro221Leu

c.662C>T · rs2044711052 · VCV1370391

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7222 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7222	likely pathogenic
REVEL	0.869	moderately pathogenic-leaning
SaProt	LLR -8.59	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 26 kb · p 4.2e-08 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GOT2
Protein: p.Pro221Leu
Coding: c.662C>T
MANE Select: NM_002080
dbSNP: rs2044711052
Type: single nucleotide variant
Location: chr16:58718236 (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.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-pro221leu (accessed [today's date]).

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