Is PIGS p.Met98Ile (c.294G>A) pathogenic?

PIGS p.Met98Ile (c.294G>A) is classified Uncertain significance in PIGS (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-14). AlphaMissense: ambiguous (0.4405); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with PIGS p.Met98Ile (c.294G>A)?

PIGS p.Met98Ile (c.294G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PIGS p.Met98Ile (c.294G>A) in the general population?

PIGS p.Met98Ile (c.294G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about PIGS p.Met98Ile (c.294G>A)?

AlphaMissense predicts ambiguous (score 0.4405) — an in-silico prediction, not a clinical call.

PIGS p.Met98Ile

c.294G>A · rs960556912 · VCV2345069

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4405 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4405	ambiguous
REVEL	0.043	moderately benign-leaning
SaProt	LLR -4.53	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 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.0022 · regional, not allelic
Overall
CADD	22.8	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000616% 9/1,461,460 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
Admixed American	0.00333%	30,010
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	75,028
South Asian	0.0011%	91,066
European (non-Finnish)	0.000254%	393,224

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: PIGS
Protein: p.Met98Ile
Coding: c.294G>A
MANE Select: NM_033198
dbSNP: rs960556912
Type: single nucleotide variant
Location: chr17:28563900 (GRCh38)
Gene constraint: LOEUF 0.76 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 4 PDB
Residue 98: a UniProt-annotated variant site (in gpibd18; almost complete loss of function; when tested in pigs-knockout cells, mediates only very partial restoration of gpi-anchored protein expression at the cell surface; strong decrease in protein level, possibly due to nonsense-mediated mrna decay)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PIGS p.Arg15Trp Uncertain significance ★★ same condition
PIGS p.Arg176Trp Uncertain significance ★★ ⚠ same condition
PIGS p.Arg355Cys Uncertain significance ★★ ⚠ same condition
PIGS p.Ser224Thr Uncertain significance ★★ ⚠ same condition
PIGS p.Tyr522Cys Uncertain significance ★★ ⚠ same condition
PIGS p.Val146Met Uncertain significance ★★ ⚠ same condition
PIGS p.Leu204Val Likely benign ★★ same condition
PIGS c.469-3C>T 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/pigs-p-met98ile (accessed [today's date]).

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