Is RAF1 p.Pro261Ala (c.781C>G) pathogenic?

RAF1 p.Pro261Ala (c.781C>G) is classified Pathogenic/Likely pathogenic in RAF1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-11-26). AlphaMissense: likely pathogenic (0.9927); Absent from gnomAD v4.1; Associated with RAF1-related disorder.

What condition is associated with RAF1 p.Pro261Ala (c.781C>G)?

RAF1 p.Pro261Ala (c.781C>G) is associated with RAF1-related disorder, Noonan syndrome 5, LEOPARD syndrome 2 (ClinVar).

How common is RAF1 p.Pro261Ala (c.781C>G) in the general population?

RAF1 p.Pro261Ala (c.781C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RAF1 p.Pro261Ala (c.781C>G)?

AlphaMissense predicts likely pathogenic (score 0.9927) — an in-silico prediction, not a clinical call.

RAF1 p.Pro261Ala

c.781C>G · rs121434594 · VCV40605

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9927 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RAF1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9927	likely pathogenic ✓ concordant with ClinVar
REVEL	0.83	moderately pathogenic-leaning
SaProt	LLR -6.09	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

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: RAF1
Protein: p.Pro261Ala
Coding: c.781C>G
MANE Select: NM_002880
dbSNP: rs121434594
Type: single nucleotide variant
Location: chr3:12604189 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 261: the 'disordered' region; a UniProt-annotated variant site (in ns5; shows in vitro greater kinase activity and enhanced mapk1 activation than wild-type); a UniProt-annotated variant site (in ns5; shows greater kinase activity and enhanced mapk1 activation than wild-type); an α-helix

Full RAF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

RAF1-related disorder

Also linked: Noonan syndrome 5 LEOPARD syndrome 2 dilated cardiomyopathy 1NN Noonan syndrome RASopathy

Similar variants

RAF1 p.Pro261Ser Pathogenic ★★★ ⚠ same residue
RAF1 p.Pro261Arg Pathogenic/Likely pathogenic ★★ ⚠ same residue
RAF1 p.Pro261His Pathogenic/Likely pathogenic ★★ ⚠ same residue
RAF1 p.Pro261Leu Pathogenic/Likely pathogenic ★★ ⚠ same residue
RAF1 p.Pro261Thr Pathogenic/Likely pathogenic ★★ ⚠ same residue
RAF1 p.Pro261= Likely benign ★ same residue
RAF1 p.Arg256Ser Likely pathogenic ★★★ ⚠ same condition
RAF1 p.Gly361Ala 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/raf1-p-pro261ala (accessed [today's date]).

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