Is RAF1 p.Cys424= (c.1272C>T) pathogenic?

RAF1 p.Cys424= (c.1272C>T) is classified Likely benign in RAF1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-15). Ultra-rare (popmax 0.0156%, eas); Associated with Cardiovascular phenotype.

What condition is associated with RAF1 p.Cys424= (c.1272C>T)?

RAF1 p.Cys424= (c.1272C>T) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is RAF1 p.Cys424= (c.1272C>T) in the general population?

RAF1 p.Cys424= (c.1272C>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

RAF1 p.Cys424=

c.1272C>T · rs142942142 · VCV379396

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Conditions

Cardiovascular phenotype

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 -3.9	GERP -5.5
Overall
CADD	2.968	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,882 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00298% 48/1,612,800 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,412
African / African-American	0.012%	8,317
European (non-Finnish)	0.00263%	38,030
Admixed American	0.00167%	59,982

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.Cys424=
Coding: c.1272C>T
MANE Select: NM_002880
dbSNP: rs142942142
Type: single nucleotide variant
Location: chr3:12590896 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 424: the protein kinase domain

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

Disease context

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

Also linked: RASopathy

Similar variants

RAF1 p.Cys424Trp Uncertain significance ★ ⚠ same residue
RAF1 p.Cys424Tyr 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
RAF1 p.Ser257Pro Likely 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-cys424 (accessed [today's date]).

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