Is FAS p.Gln276Pro (c.827A>C) pathogenic?

FAS p.Gln276Pro (c.827A>C) is classified Uncertain significance in FAS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-01). AlphaMissense: likely pathogenic (0.9476); Absent from gnomAD v4.1.

How common is FAS p.Gln276Pro (c.827A>C) in the general population?

FAS p.Gln276Pro (c.827A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FAS p.Gln276Pro (c.827A>C)?

AlphaMissense predicts likely pathogenic (score 0.9476) — an in-silico prediction, not a clinical call.

FAS p.Gln276Pro

c.827A>C · rs2119446558 · VCV1701146

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9476 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9476	likely pathogenic · top 2% in FAS
REVEL	0.726	pathogenic-leaning
SaProt	LLR -15.70	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.2, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 84 bp · p 0.00011 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FAS
Protein: p.Gln276Pro
Coding: c.827A>C
MANE Select: NM_000043
dbSNP: rs2119446558
Type: single nucleotide variant
Location: chr10:89014269 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.21 · 7 PDB
Residue 276: the death domain; the 'interaction with hipk3' region; an α-helix

Full FAS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FAS p.Gln276Glu Uncertain significance ★ ⚠ same residue
FAS p.Gln276His Uncertain significance ★ ⚠ same residue
FAS c.196+1G>A Pathogenic/Likely pathogenic ★★ same type
FAS c.443+1G>A Pathogenic/Likely pathogenic ★★ same type
FAS c.651+1G>A Pathogenic/Likely pathogenic ★★ same type
FAS c.651+2T>C Pathogenic ★★ same type
FAS p.Arg250Gln Pathogenic/Likely pathogenic ★★ same type
FAS p.Arg250Gly Likely pathogenic ★★ 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/fas-p-gln276pro (accessed [today's date]).

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