Is PIGS p.Ser224Thr (c.671G>C) pathogenic?

PIGS p.Ser224Thr (c.671G>C) is classified Uncertain significance in PIGS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-28). AlphaMissense: likely benign (0.1659); Ultra-rare (popmax 0.0142%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PIGS p.Ser224Thr (c.671G>C)?

PIGS p.Ser224Thr (c.671G>C) is associated with Inborn genetic diseases (ClinVar).

How common is PIGS p.Ser224Thr (c.671G>C) in the general population?

PIGS p.Ser224Thr (c.671G>C) is ultra-rare (popmax 0.0142%, nfe) (gnomAD).

What do computational predictors say about PIGS p.Ser224Thr (c.671G>C)?

AlphaMissense predicts likely benign (score 0.1659) — an in-silico prediction, not a clinical call.

PIGS p.Ser224Thr

c.671G>C · rs138782597 · VCV2379663

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1659 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0142%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1659	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -6.79	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.0022 · regional, not allelic
Overall
CADD	24.2	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

Grpmax group 0.0142% European (non-Finnish) · 168/1,179,904 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0118%

Overall 0.0109% 176/1,613,788 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0142%	7,023
Remaining individualsnot grpmax-eligible	0.008%	12,492
Admixed American	0.00333%	30,000
African / African-American	0.00133%	74,914

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.Ser224Thr
Coding: c.671G>C
MANE Select: NM_033198
dbSNP: rs138782597
Type: single nucleotide variant
Location: chr17:28561427 (GRCh38)
Gene constraint: LOEUF 0.76 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 4 PDB
Residue 224: 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.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
PIGS p.Ala107Thr 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-ser224thr (accessed [today's date]).

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