Is RAF1 p.Val263Asp (c.788T>A) pathogenic?

RAF1 p.Val263Asp (c.788T>A) is classified Pathogenic/Likely pathogenic in RAF1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2023-05-15). AlphaMissense: likely pathogenic (0.9971); Absent from gnomAD v4.1; Associated with RAF1-related disorder.

What condition is associated with RAF1 p.Val263Asp (c.788T>A)?

RAF1 p.Val263Asp (c.788T>A) is associated with RAF1-related disorder, Noonan syndrome 3, Noonan syndrome 5 (ClinVar).

How common is RAF1 p.Val263Asp (c.788T>A) in the general population?

RAF1 p.Val263Asp (c.788T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RAF1 p.Val263Asp (c.788T>A)?

AlphaMissense predicts likely pathogenic (score 0.9971) — an in-silico prediction, not a clinical call.

RAF1 p.Val263Asp

c.788T>A · rs397516830 · VCV496189

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9971 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RAF1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9971	likely pathogenic ✓ concordant with ClinVar
REVEL	0.675	pathogenic-leaning
SaProt	LLR -8.63	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 11	GERP 2.8, phastCons 1
Overall
CADD	31.0	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.Val263Asp
Coding: c.788T>A
MANE Select: NM_002880
dbSNP: rs397516830
Type: single nucleotide variant
Location: chr3:12604182 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 263: the 'disordered' region; a UniProt-annotated variant site (in ns5; shows in vitro greater kinase activity and enhanced mapk1 activation than wild-type)

Full RAF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

RAF1-related disorder

Also linked: Noonan syndrome 3 Noonan syndrome 5 LEOPARD syndrome 2 dilated cardiomyopathy 1NN RASopathy

Similar variants

RAF1 p.Val263Gly Likely pathogenic ★★★ ⚠ same residue
RAF1 p.Val263Ala Pathogenic/Likely pathogenic ★★ ⚠ same residue
RAF1 p.Val263= 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

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-val263asp (accessed [today's date]).

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