Is FAS p.Ser333Ile (c.998G>T) pathogenic?

FAS p.Ser333Ile (c.998G>T) is classified Uncertain significance in FAS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-18). AlphaMissense: likely benign (0.1271); Absent from gnomAD v4.1.

How common is FAS p.Ser333Ile (c.998G>T) in the general population?

FAS p.Ser333Ile (c.998G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FAS p.Ser333Ile (c.998G>T)?

AlphaMissense predicts likely benign (score 0.1271) — an in-silico prediction, not a clinical call.

FAS p.Ser333Ile

c.998G>T · VCV4908682

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1271 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1271	likely benign
REVEL	0.346	indeterminate
SaProt	LLR -7.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.02	GERP -1.7
Regional constraint	o/e 0.99	unconstrained · MANE · 143 bp · p 0.92 · regional, not allelic
Overall
CADD	9.635	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

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.Ser333Ile
Coding: c.998G>T
MANE Select: NM_000043
Type: single nucleotide variant
Location: chr10:89014440 (GRCh38)
Gene constraint: LOEUF 0.372 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 78.21 · 7 PDB
Residue 333: an α-helix

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

Similar variants

FAS p.Ser333= Likely benign ★ same residue
FAS p.Ser333Asn Likely benign ★ 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-ser333ile (accessed [today's date]).

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