Is FOS p.Pro255Ser (c.763C>T) pathogenic?

FOS p.Pro255Ser (c.763C>T) is classified Uncertain significance in FOS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). AlphaMissense: likely benign (0.0808); Ultra-rare (popmax 0.0178%, eas).

How common is FOS p.Pro255Ser (c.763C>T) in the general population?

FOS p.Pro255Ser (c.763C>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about FOS p.Pro255Ser (c.763C>T)?

AlphaMissense predicts likely benign (score 0.0808) — an in-silico prediction, not a clinical call.

FOS p.Pro255Ser

c.763C>T · VCV3279469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0808 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0808	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -6.54	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 6	GERP 0.53, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 2,438 bp · p 0.00036 · regional, not allelic
Overall
CADD	18.23	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 0.0178% East Asian · 8/44,892 alleles

Filtering AF 0.00883% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00062% 10/1,613,452 alleles · ultra-rare exomes 8/1,461,264 · genomes 2/152,188 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,612
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	8.47e-05%	1,180,034

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: FOS
Protein: p.Pro255Ser
Coding: c.763C>T
MANE Select: NM_005252
Type: single nucleotide variant
Location: chr14:75281044 (GRCh38)
Gene constraint: LOEUF 0.581 · pLI 0.87 (gnomAD)
Structure: AlphaFold pLDDT 58.48 · 3 PDB

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

Similar variants

FOS p.Lys176Asn Benign/Likely benign ★★ ⚠ same type
FOS p.Pro233= Likely benign ★★ same type
FOS p.Pro233Ala Likely benign ★★ same type
FOS p.Thr63= Benign ★★ same type
FOS p.Arg155Cys Likely pathogenic ★ same type
FOS p.Ala103Val Uncertain significance ★ ⚠ same type
FOS p.Ala184Asp Uncertain significance ★ ⚠ same type
FOS p.Ala203Val 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/fos-p-pro255ser (accessed [today's date]).

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