Is RAF1 p.Val98Ala (c.293T>C) pathogenic?

RAF1 p.Val98Ala (c.293T>C) is classified Uncertain significance in RAF1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-06). AlphaMissense: likely pathogenic (0.9584); Very rare (popmax 0.0028%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with RAF1 p.Val98Ala (c.293T>C)?

RAF1 p.Val98Ala (c.293T>C) is associated with Cardiovascular phenotype, Noonan syndrome, RASopathy (ClinVar).

How common is RAF1 p.Val98Ala (c.293T>C) in the general population?

RAF1 p.Val98Ala (c.293T>C) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about RAF1 p.Val98Ala (c.293T>C)?

AlphaMissense predicts likely pathogenic (score 0.9584) — an in-silico prediction, not a clinical call.

RAF1 p.Val98Ala

c.293T>C · rs763559779 · VCV280524

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9584 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9584	likely pathogenic
REVEL	0.866	moderately pathogenic-leaning
SaProt	LLR -11.27	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2.8, phastCons 1
Overall
CADD	27.5	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 0.0028% European (non-Finnish) · 33/1,180,030 alleles

Filtering AF 0.00199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00175%

Overall 0.00217% 35/1,614,068 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0028%	35,758
African / African-American	0.00267%	37,465

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.Val98Ala
Coding: c.293T>C
MANE Select: NM_002880
dbSNP: rs763559779
Type: single nucleotide variant
Location: chr3:12611977 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 98: the rbd domain; a β-strand

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 RASopathy

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-val98ala (accessed [today's date]).

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