Is PIGS p.Ala400Val (c.1199C>T) pathogenic?

PIGS p.Ala400Val (c.1199C>T) is classified Uncertain significance in PIGS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). AlphaMissense: likely benign (0.083); Very rare (popmax 0.00836%, amr); Associated with Inborn genetic diseases.

What condition is associated with PIGS p.Ala400Val (c.1199C>T)?

PIGS p.Ala400Val (c.1199C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PIGS p.Ala400Val (c.1199C>T) in the general population?

PIGS p.Ala400Val (c.1199C>T) is very rare (popmax 0.00836%, amr) (gnomAD).

What do computational predictors say about PIGS p.Ala400Val (c.1199C>T)?

AlphaMissense predicts likely benign (score 0.083) — an in-silico prediction, not a clinical call.

PIGS p.Ala400Val

c.1199C>T · rs754568822 · VCV3212833

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.083 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00836%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.083	likely benign
REVEL	0.072	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 5.1	GERP -0.49, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.0022 · regional, not allelic
Overall
CADD	20.6	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

Grpmax group 0.00836% Admixed American · 5/59,780 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000342% 5/1,460,458 alleles · very rare

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.Ala400Val
Coding: c.1199C>T
MANE Select: NM_033198
dbSNP: rs754568822
Type: single nucleotide variant
Location: chr17:28555044 (GRCh38)
Gene constraint: LOEUF 0.76 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 4 PDB
Residue 400: 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); an α-helix

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-ala400val (accessed [today's date]).

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