Is PIGS p.Ser121= (c.363G>A) pathogenic?

PIGS p.Ser121= (c.363G>A) is classified Likely benign in PIGS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-04). Ultra-rare (popmax 0.0123%, nfe).

How common is PIGS p.Ser121= (c.363G>A) in the general population?

PIGS p.Ser121= (c.363G>A) is ultra-rare (popmax 0.0123%, nfe) (gnomAD).

PIGS p.Ser121=

c.363G>A · rs141734737 · VCV1675663

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0123%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.39	GERP -2.2
Overall
CADD	7.415	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0123% European (non-Finnish) · 145/1,179,660 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00997%

Overall 0.0103% 166/1,613,620 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0219%	4,574
European (non-Finnish)grpmax	0.0123%	8,136
African / African-American	0.00401%	24,967
Admixed American	0.00333%	29,999
Remaining individualsnot grpmax-eligible	0.0016%	62,466
South Asian	0.0011%	91,076

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser121=
Coding: c.363G>A
MANE Select: NM_033198
dbSNP: rs141734737
Type: single nucleotide variant
Location: chr17:28563831 (GRCh38)
Gene constraint: LOEUF 0.76 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 4 PDB
Residue 121: 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-ser121 (accessed [today's date]).

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