Is GALC p.Trp331Arg (c.991T>C) pathogenic?

GALC p.Trp331Arg (c.991T>C) is classified Uncertain significance in GALC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-01). AlphaMissense: likely pathogenic (0.9861); Absent from gnomAD v4.1.

How common is GALC p.Trp331Arg (c.991T>C) in the general population?

GALC p.Trp331Arg (c.991T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GALC p.Trp331Arg (c.991T>C)?

AlphaMissense predicts likely pathogenic (score 0.9861) — an in-silico prediction, not a clinical call.

GALC p.Trp331Arg

c.991T>C · rs2139996182 · VCV1176333

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9861 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9861	likely pathogenic · top 1% in GALC
REVEL	0.84	moderately pathogenic-leaning
SaProt	LLR -13.83	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 11	GERP 2.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 58 kb · p 0.37 · regional, not allelic
Overall
CADD	28.4	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

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: GALC
Protein: p.Trp331Arg
Coding: c.991T>C
MANE Select: NM_000153
dbSNP: rs2139996182
Type: single nucleotide variant
Location: chr14:87965547 (GRCh38)
Gene constraint: LOEUF 1.019 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.56

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

Similar variants

GALC p.Trp331fs Likely pathogenic ★ same residue
GALC c.1033+1G>A Likely pathogenic ★★ same type
GALC c.1034-1G>C Pathogenic/Likely pathogenic ★★ same type
GALC c.1034-2A>G Pathogenic/Likely pathogenic ★★ same type
GALC c.1161+2T>A Likely pathogenic ★★ same type
GALC c.1251+1G>C Pathogenic/Likely pathogenic ★★ same type
GALC c.1252-1G>C Pathogenic/Likely pathogenic ★★ same type
GALC c.1338+1G>C Likely pathogenic ★★ 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/galc-p-trp331arg (accessed [today's date]).

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