Is RAF1 p.Val585= (c.1755A>G) pathogenic?

RAF1 p.Val585= (c.1755A>G) is classified Benign in RAF1 (ClinVar, Expert panel, 15 submitters; last evaluated 2017-04-18). Common (popmax 6.76%, afr) — too common for a highly-penetrant pathogenic allele; Associated with RASopathy.

What condition is associated with RAF1 p.Val585= (c.1755A>G)?

RAF1 p.Val585= (c.1755A>G) is associated with RASopathy, Noonan syndrome 5, LEOPARD syndrome 2 (ClinVar).

RAF1 p.Val585=

Q: How common is RAF1 p.Val585= (c.1755A>G) in the general population?

RAF1 p.Val585= (c.1755A>G) is common (popmax 6.76%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1755A>G · rs3730296 · VCV40626

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 15 submitters

gnomAD v4.1

Common

common (popmax 6.76%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.1755A>G (p.Val585=) variant in the RAF1 gene is 6.222% (690/10404) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

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 -0.93	GERP -5.1, phastCons 0.003
Overall
CADD	4.887	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.76% African / African-American · 5,071/75,024 alleles

Filtering AF 6.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.54%

Overall 0.362% 5,848/1,614,176 alleles · common exomes 2,880/1,461,868 · genomes 2,968/152,308 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.76%	15
Admixed American	0.54%	185
Remaining individualsnot grpmax-eligible	0.531%	188
Middle Eastern	0.297%	337
South Asian	0.0263%	3,795
European (non-Finnish)	0.00653%	15,325
East Asian	0.00446%	22,444

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.Val585=
Coding: c.1755A>G
MANE Select: NM_002880
dbSNP: rs3730296
Type: single nucleotide variant
Location: chr3:12584895 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 585: an α-helix; the protein kinase domain

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

Also linked: Noonan syndrome 5 LEOPARD syndrome 2 Noonan syndrome and Noonan-related syndrome

Similar variants

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
RAF1 p.Ser259Ala Pathogenic ★★★ ⚠ same condition
RAF1 p.Ser259Thr 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-val585 (accessed [today's date]).

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