Is PIGM p.Ala176Pro (c.526G>C) pathogenic?

PIGM p.Ala176Pro (c.526G>C) is classified Uncertain significance in PIGM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-01). AlphaMissense: likely pathogenic (0.903); Very rare (popmax 0.00119%, nfe).

How common is PIGM p.Ala176Pro (c.526G>C) in the general population?

PIGM p.Ala176Pro (c.526G>C) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about PIGM p.Ala176Pro (c.526G>C)?

AlphaMissense predicts likely pathogenic (score 0.903) — an in-silico prediction, not a clinical call.

PIGM p.Ala176Pro

c.526G>C · VCV3888798

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.903	likely pathogenic
REVEL	0.38	indeterminate
SaProt	LLR -15.18	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,268 bp · p 0.65 · regional, not allelic
Overall
CADD	31.0	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 0.00119% European (non-Finnish) · 14/1,180,038 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000867% 14/1,613,978 alleles · very rare exomes 13/1,461,894 · genomes 1/152,084 · 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: PIGM
Protein: p.Ala176Pro
Coding: c.526G>C
MANE Select: NM_145167
Type: single nucleotide variant
Location: chr1:160031214 (GRCh38)
Gene constraint: LOEUF 0.975 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.10

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

Similar variants

PIGM p.Met1Thr Likely pathogenic ★★ same type
PIGM p.Arg41Gln Uncertain significance ★★ ⚠ same type
PIGM p.Arg46Lys Uncertain significance ★★ ⚠ same type
PIGM p.Cys317Tyr Uncertain significance ★★ ⚠ same type
PIGM p.Gln334Pro Uncertain significance ★★ ⚠ same type
PIGM p.Glu217Gln Uncertain significance ★★ ⚠ same type
PIGM p.Gly20Asp Uncertain significance ★★ ⚠ same type
PIGM p.His44Tyr 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/pigm-p-ala176pro (accessed [today's date]).

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