Is GOT2 p.Leu362Phe (c.1084C>T) pathogenic?

GOT2 p.Leu362Phe (c.1084C>T) is classified Uncertain significance in GOT2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-22). AlphaMissense: likely pathogenic (0.8657); Very rare (popmax 0.00856%, nfe); Associated with developmental and epileptic encephalopathy, 82.

What condition is associated with GOT2 p.Leu362Phe (c.1084C>T)?

GOT2 p.Leu362Phe (c.1084C>T) is associated with developmental and epileptic encephalopathy, 82 (ClinVar).

How common is GOT2 p.Leu362Phe (c.1084C>T) in the general population?

GOT2 p.Leu362Phe (c.1084C>T) is very rare (popmax 0.00856%, nfe) (gnomAD).

What do computational predictors say about GOT2 p.Leu362Phe (c.1084C>T)?

AlphaMissense predicts likely pathogenic (score 0.8657) — an in-silico prediction, not a clinical call.

GOT2 p.Leu362Phe

c.1084C>T · rs753394924 · VCV2570661

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8657 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00856%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 82

Computational evidence

Protein change
AlphaMissense	0.8657	likely pathogenic
REVEL	0.852	moderately pathogenic-leaning
SaProt	LLR -13.85	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 26 kb · p 4.2e-08 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00856% European (non-Finnish) · 101/1,179,746 alleles

Filtering AF 0.00716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00668%

Overall 0.00651% 105/1,613,714 alleles · very rare exomes 102/1,461,528 · genomes 3/152,186 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00856%	11,681
African / African-American	0.00267%	37,453
East Asian	0.00223%	44,876
Remaining individualsnot grpmax-eligible	0.0016%	62,476

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.Leu362Phe
Coding: c.1084C>T
MANE Select: NM_002080
dbSNP: rs753394924
Type: single nucleotide variant
Location: chr16:58709503 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI 0.49 (gnomAD)
Structure: AlphaFold pLDDT 94.77 · 3 PDB
Residue 362: an α-helix

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

Disease context

developmental and epileptic encephalopathy, 82 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GOT2 p.Leu362= Likely benign ★ same residue
GOT2 p.Arg262Gly Likely pathogenic ★★ same condition
GOT2 p.Gly366Val Likely pathogenic ★★ same condition
GOT2 p.Ala89Ser Uncertain significance ★★ ⚠ same condition
GOT2 p.Asp190Val Uncertain significance ★★ ⚠ same condition
GOT2 p.Asp197Asn Uncertain significance ★★ ⚠ same condition
GOT2 p.Pro78Leu Uncertain significance ★★ ⚠ same condition
GOT2 p.Val294Leu 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/got2-p-leu362phe (accessed [today's date]).

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