Is RAF1 p.Pro643Ser (c.1927C>T) pathogenic?

RAF1 p.Pro643Ser (c.1927C>T) is classified Uncertain significance in RAF1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-30). AlphaMissense: likely benign (0.0669); Very rare (popmax 0.000169%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with RAF1 p.Pro643Ser (c.1927C>T)?

RAF1 p.Pro643Ser (c.1927C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is RAF1 p.Pro643Ser (c.1927C>T) in the general population?

RAF1 p.Pro643Ser (c.1927C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about RAF1 p.Pro643Ser (c.1927C>T)?

AlphaMissense predicts likely benign (score 0.0669) — an in-silico prediction, not a clinical call.

RAF1 p.Pro643Ser

c.1927C>T · rs876657967 · VCV229178

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0669 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0669	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 2.8, phastCons 1
Overall
CADD	17.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000169% European (non-Finnish) · 2/1,180,038 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,190 alleles · very rare exomes 2/1,461,894 · genomes 0/152,296 · joint denominator

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.Pro643Ser
Coding: c.1927C>T
MANE Select: NM_002880
dbSNP: rs876657967
Type: single nucleotide variant
Location: chr3:12584534 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RAF1 p.Pro643Leu Uncertain significance ★★ ⚠ same residue
RAF1 p.Pro643= Likely benign ★★ same residue
RAF1 p.Pro261His Pathogenic/Likely pathogenic ★★ ⚠ same condition
RAF1 p.Pro261Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
RAF1 c.207+5G>T Uncertain significance ★★ same condition
RAF1 c.834+4A>C Uncertain significance ★★ same condition
RAF1 c.-4A>C Uncertain significance ★★ same condition
RAF1 p.Ala119Val Uncertain significance ★★ ⚠ 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-pro643ser (accessed [today's date]).

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