Is RAF1 p.Val647= (c.1941C>T) pathogenic?

RAF1 p.Val647= (c.1941C>T) is classified Benign in RAF1 (ClinVar, Expert panel, 16 submitters; last evaluated 2017-04-18). Low-frequency (popmax 1.14%, nfe); Associated with RASopathy.

What condition is associated with RAF1 p.Val647= (c.1941C>T)?

RAF1 p.Val647= (c.1941C>T) is associated with RASopathy, Noonan syndrome 5, LEOPARD syndrome 2 (ClinVar).

How common is RAF1 p.Val647= (c.1941C>T) in the general population?

RAF1 p.Val647= (c.1941C>T) is low-frequency (popmax 1.14%, nfe) (gnomAD).

RAF1 p.Val647=

c.1941C>T · rs3730297 · VCV44623

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 16 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.14%, nfe)

Conditions

RASopathy

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.1941C>T (p.Val647=) variant in the RAF1 gene is 1.04% (738/66732) of European 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 looked up on this page · why
Constraint at this position
Conservation	phyloP 4.4	GERP 0.89, phastCons 1
Overall
CADD	4.289	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.14% European (non-Finnish) · 13,485/1,180,038 alleles

Filtering AF 1.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.12%

Overall 0.951% 15,356/1,614,198 alleles · low-frequency exomes 14,286/1,461,886 · genomes 1,070/152,312 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.14%	88
Finnishnot grpmax-eligible	0.832%	120
Remaining individualsnot grpmax-eligible	0.79%	127
Ashkenazi Jewishnot grpmax-eligible	0.665%	150
Admixed American	0.59%	170
Middle Eastern	0.33%	303
South Asian	0.18%	555
African / African-American	0.144%	695
East Asian	0.00223%	44,880

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.Val647=
Coding: c.1941C>T
MANE Select: NM_002880
dbSNP: rs3730297
Type: single nucleotide variant
Location: chr3:12584520 (GRCh38)

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

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-val647 (accessed [today's date]).

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