Is RAF1 p.Ser259Phe (c.776C>T) pathogenic?

RAF1 p.Ser259Phe (c.776C>T) is classified Pathogenic in RAF1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-19). AlphaMissense: likely pathogenic (0.9987); Absent from gnomAD v4.1; Associated with Noonan syndrome and Noonan-related syndrome.

What condition is associated with RAF1 p.Ser259Phe (c.776C>T)?

RAF1 p.Ser259Phe (c.776C>T) is associated with Noonan syndrome and Noonan-related syndrome, Noonan syndrome, RASopathy (ClinVar).

How common is RAF1 p.Ser259Phe (c.776C>T) in the general population?

RAF1 p.Ser259Phe (c.776C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RAF1 p.Ser259Phe (c.776C>T)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

RAF1 p.Ser259Phe

c.776C>T · rs397516827 · VCV40603

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Noonan syndrome and Noonan-related syndrome

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic ✓ concordant with ClinVar · top 10% in RAF1
REVEL	0.786	moderately pathogenic-leaning
SaProt	LLR -11.74	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 12	GERP 2.8, phastCons 1
Overall
CADD	33.0	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.Ser259Phe
Coding: c.776C>T
MANE Select: NM_002880
dbSNP: rs397516827
Type: single nucleotide variant
Location: chr3:12604194 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 259: a modified residue (phosphoserine; by pka, pkc and pkb/akt1); the 'disordered' region; a UniProt-annotated variant site (in an ovarian serous carcinoma sample; somatic mutation; increased erk activation); a UniProt-annotated variant site (in ns5)

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

Disease context

Noonan syndrome and Noonan-related syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Noonan syndrome RASopathy

Similar variants

RAF1 p.Ser259Ala Pathogenic ★★★ ⚠ same residue
RAF1 p.Ser259Thr Pathogenic ★★★ ⚠ same residue
RAF1 p.Ser259Tyr Pathogenic ★★★ same residue
RAF1 p.Ser259Cys Pathogenic/Likely pathogenic ★★ same residue
RAF1 p.Ser259Pro Pathogenic/Likely pathogenic ★★ ⚠ same residue
RAF1 p.Ser259_Thr260delinsArgAla Likely pathogenic same residue
RAF1 p.Arg256Ser Likely pathogenic ★★★ ⚠ same condition
RAF1 p.Gly361Ala 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-ser259phe (accessed [today's date]).

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