Is PIGS p.Arg545His (c.1634G>A) pathogenic?

PIGS p.Arg545His (c.1634G>A) is classified Likely benign in PIGS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-01). AlphaMissense: likely benign (0.1021); Rare (popmax 0.904%, sas).

How common is PIGS p.Arg545His (c.1634G>A) in the general population?

PIGS p.Arg545His (c.1634G>A) is rare (popmax 0.904%, sas) (gnomAD).

What do computational predictors say about PIGS p.Arg545His (c.1634G>A)?

AlphaMissense predicts likely benign (score 0.1021) — an in-silico prediction, not a clinical call.

PIGS p.Arg545His

c.1634G>A · rs202057961 · VCV2647579

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1021 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.904%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1021	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -10.85	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.003	GERP -3.3, phastCons 0.82
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 0.0022 · regional, not allelic
Overall
CADD	17.31	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 0.904% South Asian · 823/91,072 alleles

Filtering AF 0.852% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.832%

Overall 0.0547% 883/1,614,100 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.904%	111
Remaining individualsnot grpmax-eligible	0.0736%	1,359
Middle Eastern	0.0166%	6,040
African / African-American	0.00267%	37,508
European (non-Finnish)	0.000932%	107,273

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.Arg545His
Coding: c.1634G>A
MANE Select: NM_033198
dbSNP: rs202057961
Type: single nucleotide variant
Location: chr17:28554254 (GRCh38)
Gene constraint: LOEUF 0.76 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 4 PDB
Residue 545: 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.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
PIGS c.1080+15A>G Likely benign ★★ 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-arg545his (accessed [today's date]).

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