Is FAS p.Val83Met (c.247G>A) pathogenic?

FAS p.Val83Met (c.247G>A) is classified Uncertain significance in FAS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-23). AlphaMissense: likely benign (0.1381); Very rare (popmax 0.00834%, amr); Associated with autoimmune lymphoproliferative syndrome type 1.

What condition is associated with FAS p.Val83Met (c.247G>A)?

FAS p.Val83Met (c.247G>A) is associated with autoimmune lymphoproliferative syndrome type 1 (ClinVar).

How common is FAS p.Val83Met (c.247G>A) in the general population?

FAS p.Val83Met (c.247G>A) is very rare (popmax 0.00834%, amr) (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.Val83Met (c.247G>A)?

AlphaMissense predicts likely benign (score 0.1381) — an in-silico prediction, not a clinical call.

FAS p.Val83Met

c.247G>A · rs199790261 · VCV1001817

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1381 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoimmune lymphoproliferative syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.1381	likely benign
REVEL	0.266	benign-leaning
SaProt	LLR -9.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -1.1
Regional constraint	o/e 0.92	unconstrained · MANE · 23 kb · p 0.16 · regional, not allelic
Overall
CADD	13.63	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 0.00834% Admixed American · 5/59,984 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00192% 31/1,613,996 alleles · very rare exomes 26/1,461,758 · genomes 5/152,238 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,997
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,798
East Asian	0.00446%	22,443
African / African-American	0.00267%	37,500
South Asian	0.0022%	45,538
European (non-Finnish)	0.00153%	65,553

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: FAS
Protein: p.Val83Met
Coding: c.247G>A
MANE Select: NM_000043
dbSNP: rs199790261
Type: single nucleotide variant
Location: chr10:89007750 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.21 · 7 PDB
Residue 83: a β-strand

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.Val83= Likely benign ★ same residue
FAS c.651+1G>A Pathogenic/Likely pathogenic ★★ same condition
FAS c.651+2T>C Pathogenic ★★ same condition
FAS p.Arg250Gln Pathogenic/Likely pathogenic ★★ same condition
FAS p.Arg250Gly Likely pathogenic ★★ same condition
FAS p.Arg250Ter Pathogenic/Likely pathogenic ★★ same condition
FAS p.Asp260Asn Pathogenic ★★ ⚠ same condition
FAS p.Cys135Tyr 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-val83met (accessed [today's date]).

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