Is PIGS p.Leu262= (c.786C>T) pathogenic?

PIGS p.Leu262= (c.786C>T) is classified Likely benign in PIGS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-01). Very rare (popmax 0.00882%, sas).

How common is PIGS p.Leu262= (c.786C>T) in the general population?

PIGS p.Leu262= (c.786C>T) is very rare (popmax 0.00882%, sas) (gnomAD).

PIGS p.Leu262=

c.786C>T · VCV4934339

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00882%, sas)

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 3.2	GERP -1.6, phastCons 1
Overall
CADD	12.62	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00882% South Asian · 8/90,736 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.00136% 22/1,612,422 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00882%	11,342
Remaining individualsnot grpmax-eligible	0.00641%	15,612
East Asian	0.00446%	22,407
African / African-American	0.00133%	74,950
European (non-Finnish)	0.000594%	168,476

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.Leu262=
Coding: c.786C>T
MANE Select: NM_033198
Type: single nucleotide variant
Location: chr17:28560082 (GRCh38)
Gene constraint: LOEUF 0.76 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 4 PDB
Residue 262: 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

Similar variants

PIGS p.Leu262Phe 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-leu262 (accessed [today's date]).

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