Is PIGS p.Arg109Trp (c.325C>T) pathogenic?

PIGS p.Arg109Trp (c.325C>T) is classified Uncertain significance in PIGS (ClinVar, Single submitter, 1 submitter; last evaluated 2026-07-08). AlphaMissense: ambiguous (0.3509); Very rare (popmax 0.00966%, nfe).

How common is PIGS p.Arg109Trp (c.325C>T) in the general population?

PIGS p.Arg109Trp (c.325C>T) is very rare (popmax 0.00966%, nfe) (gnomAD).

What do computational predictors say about PIGS p.Arg109Trp (c.325C>T)?

AlphaMissense predicts ambiguous (score 0.3509) — an in-silico prediction, not a clinical call.

PIGS p.Arg109Trp

c.325C>T · VCV3907715

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3509 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00966%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3509	ambiguous
REVEL	0.365	indeterminate
SaProt	LLR -13.99	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.0022 · regional, not allelic
Overall
CADD	29.5	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 0.00966% European (non-Finnish) · 114/1,180,012 alleles

Filtering AF 0.00817% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00761%

Overall 0.00743% 120/1,614,020 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00966%	10,351
African / African-American	0.004%	24,971
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asian	0.0022%	45,545

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.Arg109Trp
Coding: c.325C>T
MANE Select: NM_033198
Type: single nucleotide variant
Location: chr17:28563869 (GRCh38)
Gene constraint: LOEUF 0.76 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 4 PDB
Residue 109: 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

Similar variants

PIGS p.Arg109Gln Uncertain significance ★ ⚠ same residue
PIGS p.Arg15Trp Uncertain significance ★★ same type
PIGS p.Arg176Trp Uncertain significance ★★ ⚠ same type
PIGS p.Arg355Cys Uncertain significance ★★ ⚠ same type
PIGS p.Pro402Ser Uncertain significance ★★ ⚠ same type
PIGS p.Ser224Thr Uncertain significance ★★ ⚠ same type
PIGS p.Tyr522Cys Uncertain significance ★★ ⚠ same type
PIGS p.Val146Met Uncertain significance ★★ ⚠ same type

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-arg109trp (accessed [today's date]).

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