Is PIGS p.Val74Met (c.220G>A) pathogenic?

PIGS p.Val74Met (c.220G>A) is classified Uncertain significance in PIGS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-07). AlphaMissense: likely benign (0.1278); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PIGS p.Val74Met (c.220G>A)?

PIGS p.Val74Met (c.220G>A) is associated with Inborn genetic diseases (ClinVar).

How common is PIGS p.Val74Met (c.220G>A) in the general population?

PIGS p.Val74Met (c.220G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PIGS p.Val74Met (c.220G>A)?

AlphaMissense predicts likely benign (score 0.1278) — an in-silico prediction, not a clinical call.

PIGS p.Val74Met

c.220G>A · VCV4627586

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1278 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1278	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -6.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.64	GERP 1.5, phastCons 0.13
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.0022 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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: PIGS
Protein: p.Val74Met
Coding: c.220G>A
MANE Select: NM_033198
Type: single nucleotide variant
Location: chr17:28570918 (GRCh38)
Gene constraint: LOEUF 0.76 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 4 PDB
Residue 74: 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-val74met (accessed [today's date]).

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