Is PIGS p.Arg394Trp (c.1180C>T) pathogenic?

PIGS p.Arg394Trp (c.1180C>T) is classified Uncertain significance in PIGS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-19). AlphaMissense: ambiguous (0.5229); Ultra-rare (popmax 0.0227%, afr); Associated with Inborn genetic diseases.

What condition is associated with PIGS p.Arg394Trp (c.1180C>T)?

PIGS p.Arg394Trp (c.1180C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PIGS p.Arg394Trp (c.1180C>T) in the general population?

PIGS p.Arg394Trp (c.1180C>T) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about PIGS p.Arg394Trp (c.1180C>T)?

AlphaMissense predicts ambiguous (score 0.5229) — an in-silico prediction, not a clinical call.

PIGS p.Arg394Trp

c.1180C>T · rs187505358 · VCV2397874

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5229 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5229	ambiguous
REVEL	0.473	indeterminate
SaProt	LLR -14.51	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.21 · evaluated, not missing
Pangolin	Δ0.22	loss · gain 0.01 · SpliceAI below 0.2 · independent
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	32.0	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 0.0227% African / African-American · 17/74,890 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00422% 68/1,611,548 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,405
Admixed American	0.0167%	6,001
East Asian	0.00446%	22,422
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,592
European (non-Finnish)	0.00323%	30,994

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.Arg394Trp
Coding: c.1180C>T
MANE Select: NM_033198
dbSNP: rs187505358
Type: single nucleotide variant
Location: chr17:28556167 (GRCh38)
Gene constraint: LOEUF 0.76 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 4 PDB
Residue 394: 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-arg394trp (accessed [today's date]).

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