Is FOS p.Pro228Ala (c.682C>G) pathogenic?

FOS p.Pro228Ala (c.682C>G) is classified Uncertain significance in FOS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). AlphaMissense: likely benign (0.0601); Ultra-rare (popmax 0.0337%, nfe).

How common is FOS p.Pro228Ala (c.682C>G) in the general population?

FOS p.Pro228Ala (c.682C>G) is ultra-rare (popmax 0.0337%, nfe) (gnomAD).

What do computational predictors say about FOS p.Pro228Ala (c.682C>G)?

AlphaMissense predicts likely benign (score 0.0601) — an in-silico prediction, not a clinical call.

FOS p.Pro228Ala

c.682C>G · rs200077622 · VCV2345523

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0601 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0337%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0601	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -6.27	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 1.3	GERP 0.36, phastCons 0.99
Regional constraint	o/e 0.84	unconstrained · MANE · 2,438 bp · p 0.00036 · regional, not allelic
Overall
CADD	17.56	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 0.0337% European (non-Finnish) · 398/1,180,026 alleles

Filtering AF 0.0309% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.0299% 482/1,614,054 alleles · ultra-rare exomes 450/1,461,886 · genomes 32/152,168 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.145%	689
Remaining individualsnot grpmax-eligible	0.0368%	2,717
European (non-Finnish)grpmax	0.0337%	2,965
Admixed American	0.02%	5,001
African / African-American	0.00534%	18,728
Finnishnot grpmax-eligible	0.00312%	32,016

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro228Ala
Coding: c.682C>G
MANE Select: NM_005252
dbSNP: rs200077622
Type: single nucleotide variant
Location: chr14:75280963 (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-pro228ala (accessed [today's date]).

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