Is RAF1 p.Arg40Cys (c.118C>T) pathogenic?

RAF1 p.Arg40Cys (c.118C>T) is classified Likely benign in RAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-08). AlphaMissense: likely benign (0.3204); Ultra-rare (popmax 0.0183%, amr); Associated with RASopathy.

What condition is associated with RAF1 p.Arg40Cys (c.118C>T)?

RAF1 p.Arg40Cys (c.118C>T) is associated with RASopathy (ClinVar).

How common is RAF1 p.Arg40Cys (c.118C>T) in the general population?

RAF1 p.Arg40Cys (c.118C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about RAF1 p.Arg40Cys (c.118C>T)?

AlphaMissense predicts likely benign (score 0.3204) — an in-silico prediction, not a clinical call.

RAF1 p.Arg40Cys

c.118C>T · rs772390935 · VCV477673

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3204 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.3204	likely benign
REVEL	0.455	indeterminate
SaProt	LLR -9.31	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Overall
CADD	32.0	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

Grpmax group 0.0183% Admixed American · 11/60,014 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.000821% 12/1,461,886 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0183%	5,456
African / African-American	0.00133%	75,032

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: RAF1
Protein: p.Arg40Cys
Coding: c.118C>T
MANE Select: NM_002880
dbSNP: rs772390935
Type: single nucleotide variant
Location: chr3:12618604 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB

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

Disease context

RASopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RAF1 p.Arg40His Benign ★★★ same residue
RAF1 p.Arg40= Likely benign ★ same residue
RAF1 p.Arg40Leu Uncertain significance ★ same residue
RAF1 p.Arg256Ser Likely pathogenic ★★★ ⚠ same condition
RAF1 p.Gly361Ala Pathogenic ★★★ ⚠ same condition
RAF1 p.Leu613Val Pathogenic ★★★ same condition
RAF1 p.Pro261Ser Pathogenic ★★★ ⚠ same condition
RAF1 p.Ser257Leu 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-arg40cys (accessed [today's date]).

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