Is GNMT p.Trp48Arg (c.142T>C) pathogenic?

GNMT p.Trp48Arg (c.142T>C) is classified Uncertain significance in GNMT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-30). AlphaMissense: likely pathogenic (0.9635); Very rare (popmax 0.000173%, nfe).

How common is GNMT p.Trp48Arg (c.142T>C) in the general population?

GNMT p.Trp48Arg (c.142T>C) is very rare (popmax 0.000173%, nfe) (gnomAD).

What do computational predictors say about GNMT p.Trp48Arg (c.142T>C)?

AlphaMissense predicts likely pathogenic (score 0.9635) — an in-silico prediction, not a clinical call.

GNMT p.Trp48Arg

c.142T>C · rs1055158308 · VCV1957298

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9635 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000173%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9635	likely pathogenic
REVEL	0.766	pathogenic-leaning
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 1,472 bp · p 0.22 · regional, not allelic
Overall
CADD	29.9	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 0.000173% European (non-Finnish) · 2/1,158,108 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00064% 10/1,562,716 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0278%	3,601
European (non-Finnish)grpmax	0.000173%	579,056

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Trp48Arg
Coding: c.142T>C
MANE Select: NM_018960
dbSNP: rs1055158308
Type: single nucleotide variant
Location: chr6:42960909 (GRCh38)
Gene constraint: LOEUF 1.328 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.75 · 3 PDB
Residue 48: an α-helix

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.Ala216Ser Uncertain significance ★ ⚠ same type
GNMT p.Glu114Lys Uncertain significance ★ same type
GNMT p.Ile283Val Conflicting classifications of pathogenicity ★ ⚠ 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-trp48arg (accessed [today's date]).

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