Is RAF1 p.Arg40= (c.120C>T) pathogenic?

RAF1 p.Arg40= (c.120C>T) is classified Likely benign in RAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-07-09). Very rare (popmax 0.00133%, afr); Associated with RASopathy.

What condition is associated with RAF1 p.Arg40= (c.120C>T)?

RAF1 p.Arg40= (c.120C>T) is associated with RASopathy (ClinVar).

How common is RAF1 p.Arg40= (c.120C>T) in the general population?

RAF1 p.Arg40= (c.120C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

RAF1 p.Arg40=

c.120C>T · rs1356157276 · VCV1099771

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

RASopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.52	GERP -5, phastCons 0.98
Overall
CADD	7.499	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,050 alleles

Overall 0.000186% 3/1,614,164 alleles · very rare exomes 3/1,461,894 · genomes 0/152,270 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,050
South Asian	0.0011%	91,084
European (non-Finnish)	8.47e-05%	1,180,025

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.Arg40=
Coding: c.120C>T
MANE Select: NM_002880
dbSNP: rs1356157276
Type: single nucleotide variant
Location: chr3:12618602 (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.Arg40Cys 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-arg40 (accessed [today's date]).

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