Is RAF1 p.Pro623Ser (c.1867C>T) pathogenic?

RAF1 p.Pro623Ser (c.1867C>T) is classified Uncertain significance in RAF1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-30). AlphaMissense: likely pathogenic (0.9988); Very rare (popmax 0.000169%, nfe); Associated with LEOPARD syndrome 2.

What condition is associated with RAF1 p.Pro623Ser (c.1867C>T)?

RAF1 p.Pro623Ser (c.1867C>T) is associated with LEOPARD syndrome 2, Noonan syndrome 5, dilated cardiomyopathy 1NN (ClinVar).

How common is RAF1 p.Pro623Ser (c.1867C>T) in the general population?

RAF1 p.Pro623Ser (c.1867C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about RAF1 p.Pro623Ser (c.1867C>T)?

AlphaMissense predicts likely pathogenic (score 0.9988) — an in-silico prediction, not a clinical call.

RAF1 p.Pro623Ser

c.1867C>T · rs373596121 · VCV393135

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

LEOPARD syndrome 2

Computational evidence

Protein change
AlphaMissense	0.9988	likely pathogenic · top 10% in RAF1
REVEL	0.602	indeterminate
SaProt	LLR -7.71	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 12	GERP 2.8, phastCons 1
Overall
CADD	27.7	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 0.000169% European (non-Finnish) · 2/1,180,006 alleles

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

Overall 0.000137% 2/1,461,842 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.Pro623Ser
Coding: c.1867C>T
MANE Select: NM_002880
dbSNP: rs373596121
Type: single nucleotide variant
Location: chr3:12584594 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 623: an α-helix

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

Disease context

LEOPARD syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Noonan syndrome 5 dilated cardiomyopathy 1NN RASopathy

Similar variants

RAF1 p.Pro623= 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
RAF1 p.Ser257Pro Likely pathogenic ★★★ ⚠ same condition
RAF1 p.Ser259Ala 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-pro623ser (accessed [today's date]).

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