Is RAF1 p.Val379Phe (c.1135G>T) pathogenic?

RAF1 p.Val379Phe (c.1135G>T) is classified Uncertain significance in RAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-05). AlphaMissense: likely pathogenic (0.9714); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with RAF1 p.Val379Phe (c.1135G>T)?

RAF1 p.Val379Phe (c.1135G>T) is associated with RASopathy (ClinVar).

How common is RAF1 p.Val379Phe (c.1135G>T) in the general population?

RAF1 p.Val379Phe (c.1135G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RAF1 p.Val379Phe (c.1135G>T)?

AlphaMissense predicts likely pathogenic (score 0.9714) — an in-silico prediction, not a clinical call.

RAF1 p.Val379Phe

c.1135G>T · rs2125347802 · VCV1722191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9714 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.9714	likely pathogenic
REVEL	0.736	pathogenic-leaning
SaProt	LLR -9.71	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RAF1
Protein: p.Val379Phe
Coding: c.1135G>T
MANE Select: NM_002880
dbSNP: rs2125347802
Type: single nucleotide variant
Location: chr3:12591766 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 379: 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

Similar variants

RAF1 p.Val379= Likely benign ★★ 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
RAF1 p.Ser259Ala 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-val379phe (accessed [today's date]).

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