Is RAF1 p.Ser605Phe (c.1814C>T) pathogenic?

RAF1 p.Ser605Phe (c.1814C>T) is classified Conflicting classifications of pathogenicity in RAF1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-16). AlphaMissense: likely pathogenic (0.7919); Very rare (popmax 0.00915%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with RAF1 p.Ser605Phe (c.1814C>T)?

RAF1 p.Ser605Phe (c.1814C>T) is associated with Cardiovascular phenotype, Noonan syndrome 5, LEOPARD syndrome 2 (ClinVar).

How common is RAF1 p.Ser605Phe (c.1814C>T) in the general population?

RAF1 p.Ser605Phe (c.1814C>T) is very rare (popmax 0.00915%, nfe) (gnomAD).

What do computational predictors say about RAF1 p.Ser605Phe (c.1814C>T)?

AlphaMissense predicts likely pathogenic (score 0.7919) — an in-silico prediction, not a clinical call.

RAF1 p.Ser605Phe

c.1814C>T · rs730881004 · VCV181512

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7919 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00915%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.7919	likely pathogenic
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -6.85	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 12	GERP 2.8, phastCons 1
Overall
CADD	29.5	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

Grpmax group 0.00915% European (non-Finnish) · 108/1,180,020 alleles

Filtering AF 0.00774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00719%

Overall 0.00725% 117/1,614,010 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00915%	10,926
Finnishnot grpmax-eligible	0.00781%	12,806
Remaining individualsnot grpmax-eligible	0.0032%	31,240
African / African-American	0.00267%	37,455

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.Ser605Phe
Coding: c.1814C>T
MANE Select: NM_002880
dbSNP: rs730881004
Type: single nucleotide variant
Location: chr3:12584647 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 605: an α-helix; the protein kinase domain

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 5 LEOPARD syndrome 2 dilated cardiomyopathy 1NN 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-ser605phe (accessed [today's date]).

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