Is FAS p.Arg250Pro (c.749G>C) pathogenic?

FAS p.Arg250Pro (c.749G>C) is classified Pathogenic in FAS (ClinVar, Single submitter, 4 submitters; last evaluated 2025-10-21). AlphaMissense: likely pathogenic (0.9859); Absent from gnomAD v4.1; Associated with autoimmune lymphoproliferative syndrome type 1.

What condition is associated with FAS p.Arg250Pro (c.749G>C)?

FAS p.Arg250Pro (c.749G>C) is associated with autoimmune lymphoproliferative syndrome type 1 (ClinVar).

How common is FAS p.Arg250Pro (c.749G>C) in the general population?

FAS p.Arg250Pro (c.749G>C) is absent from gnomAD v4.1 (gnomAD).

How is Autoimmune lymphoproliferative syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FAS p.Arg250Pro (c.749G>C)?

AlphaMissense predicts likely pathogenic (score 0.9859) — an in-silico prediction, not a clinical call.

FAS p.Arg250Pro

c.749G>C · rs121913080 · VCV16505

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9859 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoimmune lymphoproliferative syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.9859	likely pathogenic ✓ concordant with ClinVar · top 1% in FAS
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -15.82	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 0.92	unconstrained · MANE · 23 kb · p 0.16 · regional, not allelic
Overall
CADD	25.9	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

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.Arg250Pro
Coding: c.749G>C
MANE Select: NM_000043
dbSNP: rs121913080
Type: single nucleotide variant
Location: chr10:89014191 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.21 · 7 PDB
Residue 250: the 'interaction with calm' region; a UniProt-annotated variant site (in alps1a); a UniProt-annotated variant site (in alps1a; no effect on interaction with fadd); the death domain; the 'interaction with hipk3' region

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

Disease context

autoimmune lymphoproliferative syndrome type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autoimmune lymphoproliferative syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

FAS p.Arg250Gln Pathogenic/Likely pathogenic ★★ same residue
FAS p.Arg250Gly Likely pathogenic ★★ same residue
FAS p.Arg250Ter Pathogenic/Likely pathogenic ★★ same residue
FAS c.651+1G>A Pathogenic/Likely pathogenic ★★ same condition
FAS c.651+2T>C Pathogenic ★★ same condition
FAS p.Asp260Asn Pathogenic ★★ ⚠ same condition
FAS p.Cys135Tyr Likely pathogenic ★★ same condition
FAS p.Glu272Lys Pathogenic/Likely pathogenic ★★ 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/fas-p-arg250pro (accessed [today's date]).

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