Is PIGM p.Pro348Ala (c.1042C>G) pathogenic?

PIGM p.Pro348Ala (c.1042C>G) is classified Uncertain significance in PIGM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-25). AlphaMissense: ambiguous (0.3718); Rare (popmax 0.158%, amr); Associated with hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency.

What condition is associated with PIGM p.Pro348Ala (c.1042C>G)?

PIGM p.Pro348Ala (c.1042C>G) is associated with hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency (ClinVar).

How common is PIGM p.Pro348Ala (c.1042C>G) in the general population?

PIGM p.Pro348Ala (c.1042C>G) is rare (popmax 0.158%, amr) (gnomAD).

What do computational predictors say about PIGM p.Pro348Ala (c.1042C>G)?

AlphaMissense predicts ambiguous (score 0.3718) — an in-silico prediction, not a clinical call.

PIGM p.Pro348Ala

Q: How is Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1042C>G · rs201082832 · VCV1020292

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3718 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.158%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency

Computational evidence

Protein change
AlphaMissense	0.3718	ambiguous
REVEL	0.242	benign-leaning
SaProt	LLR -8.74	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 1,268 bp · p 0.65 · regional, not allelic
Overall
CADD	22.5	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 0.158% Admixed American · 95/60,030 alleles

Filtering AF 0.132% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.123%

Overall 0.00997% 161/1,614,062 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.158%	632
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00509%	19,665
Remaining individualsnot grpmax-eligible	0.0048%	20,835
African / African-American	0.00133%	75,054
South Asian	0.0011%	91,074

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.Pro348Ala
Coding: c.1042C>G
MANE Select: NM_145167
dbSNP: rs201082832
Type: single nucleotide variant
Location: chr1:160030698 (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

Disease context

hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PIGM p.Pro348Ser Benign ★ same residue
PIGM p.Met1Thr Likely pathogenic ★★ same condition
PIGM p.Arg41Gln Uncertain significance ★★ ⚠ same condition
PIGM p.Arg46Lys Uncertain significance ★★ ⚠ same condition
PIGM p.Cys317Tyr Uncertain significance ★★ ⚠ same condition
PIGM p.Gln334Pro Uncertain significance ★★ ⚠ same condition
PIGM p.Glu217Gln Uncertain significance ★★ ⚠ same condition
PIGM p.Gly20Asp 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/pigm-p-pro348ala (accessed [today's date]).

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