Is GNMT p.Ala216Ser (c.646G>T) pathogenic?

GNMT p.Ala216Ser (c.646G>T) is classified Uncertain significance in GNMT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.1493); Very rare (popmax 0.00501%, amr).

How common is GNMT p.Ala216Ser (c.646G>T) in the general population?

GNMT p.Ala216Ser (c.646G>T) is very rare (popmax 0.00501%, amr) (gnomAD).

What do computational predictors say about GNMT p.Ala216Ser (c.646G>T)?

AlphaMissense predicts likely benign (score 0.1493) — an in-silico prediction, not a clinical call.

GNMT p.Ala216Ser

c.646G>T · VCV4264713

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1493 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1493	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -7.49	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 6.5	GERP 0.43, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,406 bp · p 0.056 · regional, not allelic
Overall
CADD	21.8	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 0.00501% Admixed American · 3/59,940 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,613,754 alleles · very rare exomes 3/1,461,594 · genomes 0/152,160 · joint denominator

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: GNMT
Protein: p.Ala216Ser
Coding: c.646G>T
MANE Select: NM_018960
Type: single nucleotide variant
Location: chr6:42963379 (GRCh38)
Gene constraint: LOEUF 1.328 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.75 · 3 PDB
Residue 216: a β-strand

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

Similar variants

GNMT p.Ala144Thr Uncertain significance ★ ⚠ same type
GNMT p.Glu114Lys Uncertain significance ★ same type
GNMT p.Ile283Val Conflicting classifications of pathogenicity ★ ⚠ same type
GNMT p.Trp48Arg Uncertain significance ★ ⚠ same type
GNMT p.Gly229= Likely benign ★ 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/gnmt-p-ala216ser (accessed [today's date]).

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