Is FOSB p.Ser253Arg (c.759C>A) pathogenic?

FOSB p.Ser253Arg (c.759C>A) is classified Uncertain significance in FOSB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-09). AlphaMissense: likely benign (0.2768); Ultra-rare (popmax 0.0186%, nfe).

How common is FOSB p.Ser253Arg (c.759C>A) in the general population?

FOSB p.Ser253Arg (c.759C>A) is ultra-rare (popmax 0.0186%, nfe) (gnomAD).

What do computational predictors say about FOSB p.Ser253Arg (c.759C>A)?

AlphaMissense predicts likely benign (score 0.2768) — an in-silico prediction, not a clinical call.

FOSB p.Ser253Arg

c.759C>A · rs151110067 · VCV2509910

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2768 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0186%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2768	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -8.80	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 4.9	GERP 0.53, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 373 bp · p 0.091 · regional, not allelic
Overall
CADD	20.1	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 0.0186% European (non-Finnish) · 220/1,179,930 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0158%

Overall 0.0143% 230/1,613,778 alleles · ultra-rare exomes 213/1,461,530 · genomes 17/152,248 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0186%	5,363
Remaining individualsnot grpmax-eligible	0.008%	12,495
African / African-American	0.00667%	14,988

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: FOSB
Protein: p.Ser253Arg
Coding: c.759C>A
MANE Select: NM_006732
dbSNP: rs151110067
Type: single nucleotide variant
Location: chr19:45472754 (GRCh38)
Gene constraint: LOEUF 0.534 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 60.79 · 12 PDB
Residue 253: the 'disordered' region

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

Similar variants

FOSB p.Pro220= Likely benign ★★ same type
FOSB p.Ala313Thr Uncertain significance ★ ⚠ same type
FOSB p.Ala313Val Uncertain significance ★ ⚠ same type
FOSB p.Ala337Thr Uncertain significance ★ ⚠ same type
FOSB p.Arg139Gln Uncertain significance ★ ⚠ same type
FOSB p.Arg139Gly Uncertain significance ★ ⚠ same type
FOSB p.Asp181Asn Uncertain significance ★ ⚠ same type
FOSB p.Asp181Glu 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/fosb-p-ser253arg (accessed [today's date]).

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