Is RAF1 p.Arg495Cys (c.1483C>T) pathogenic?

RAF1 p.Arg495Cys (c.1483C>T) is classified Uncertain significance in RAF1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-16). AlphaMissense: likely pathogenic (0.864); Very rare (popmax 0.00223%, eas); Associated with Cardiovascular phenotype.

What condition is associated with RAF1 p.Arg495Cys (c.1483C>T)?

RAF1 p.Arg495Cys (c.1483C>T) is associated with Cardiovascular phenotype, Noonan syndrome 5, LEOPARD syndrome 2 (ClinVar).

How common is RAF1 p.Arg495Cys (c.1483C>T) in the general population?

RAF1 p.Arg495Cys (c.1483C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about RAF1 p.Arg495Cys (c.1483C>T)?

AlphaMissense predicts likely pathogenic (score 0.864) — an in-silico prediction, not a clinical call.

RAF1 p.Arg495Cys

c.1483C>T · rs941573221 · VCV2148191

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.864 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.864	likely pathogenic
REVEL	0.569	indeterminate
SaProt	LLR -12.99	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 2.8, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00223% East Asian · 1/44,888 alleles

Overall 0.000248% 4/1,614,176 alleles · very rare exomes 4/1,461,852 · genomes 0/152,324 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,888
Finnishnot grpmax-eligible	0.00156%	64,022
South Asian	0.0011%	91,088
European (non-Finnish)	8.47e-05%	1,180,018

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.Arg495Cys
Coding: c.1483C>T
MANE Select: NM_002880
dbSNP: rs941573221
Type: single nucleotide variant
Location: chr3:12585734 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 495: a turn; 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: Noonan syndrome 5 LEOPARD syndrome 2 dilated cardiomyopathy 1NN RASopathy

Similar variants

RAF1 p.Arg495= Likely benign ★ same residue
RAF1 p.Arg495His 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-arg495cys (accessed [today's date]).

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