Is RAF1 p.Phe648Ser (c.1943T>C) pathogenic?

RAF1 p.Phe648Ser (c.1943T>C) is classified Uncertain significance in RAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-03). AlphaMissense: likely pathogenic (0.8141); Very rare (popmax 0.000508%, nfe); Associated with RASopathy.

What condition is associated with RAF1 p.Phe648Ser (c.1943T>C)?

RAF1 p.Phe648Ser (c.1943T>C) is associated with RASopathy (ClinVar).

How common is RAF1 p.Phe648Ser (c.1943T>C) in the general population?

RAF1 p.Phe648Ser (c.1943T>C) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about RAF1 p.Phe648Ser (c.1943T>C)?

AlphaMissense predicts likely pathogenic (score 0.8141) — an in-silico prediction, not a clinical call.

RAF1 p.Phe648Ser

c.1943T>C · rs760591831 · VCV1497081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8141 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.8141	likely pathogenic
REVEL	0.49	indeterminate
SaProt	LLR -4.40	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
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	24.4	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 0.000508% European (non-Finnish) · 6/1,180,040 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,890 alleles · very rare

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.Phe648Ser
Coding: c.1943T>C
MANE Select: NM_002880
dbSNP: rs760591831
Type: single nucleotide variant
Location: chr3:12584518 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB

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.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-phe648ser (accessed [today's date]).

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