Is RAF1 p.Pro308Leu (c.923C>T) pathogenic?

RAF1 p.Pro308Leu (c.923C>T) is classified Benign in RAF1 (ClinVar, Expert panel, 13 submitters; last evaluated 2017-04-18). AlphaMissense: likely benign (0.0951); Low-frequency (popmax 1.87%, afr); Associated with RASopathy.

What condition is associated with RAF1 p.Pro308Leu (c.923C>T)?

RAF1 p.Pro308Leu (c.923C>T) is associated with RASopathy, Noonan syndrome 5, LEOPARD syndrome 2 (ClinVar).

How common is RAF1 p.Pro308Leu (c.923C>T) in the general population?

RAF1 p.Pro308Leu (c.923C>T) is low-frequency (popmax 1.87%, afr) (gnomAD).

What do computational predictors say about RAF1 p.Pro308Leu (c.923C>T)?

AlphaMissense predicts likely benign (score 0.0951) — an in-silico prediction, not a clinical call.

RAF1 p.Pro308Leu

c.923C>T · rs5746220 · VCV40611

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 13 submitters

AlphaMissense

likely benign

0.0951 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.87%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.923C>T (p.Pro308Leu) variant in the RAF1 gene is 1.516% (179/10394) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0951	likely benign
REVEL	0.353	indeterminate
SaProt	LLR -7.44	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Overall
CADD	24.9	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 1.87% African / African-American · 1,400/75,018 alleles

Filtering AF 1.78% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.75%

Overall 0.0978% 1,579/1,614,118 alleles · low-frequency exomes 787/1,461,888 · genomes 792/152,230 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.87%	54
Remaining individualsnot grpmax-eligible	0.139%	718
Admixed American	0.11%	909
Middle Eastern	0.099%	1,010
South Asian	0.00878%	11,386
European (non-Finnish)	0.00102%	98,336

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.Pro308Leu
Coding: c.923C>T
MANE Select: NM_002880
dbSNP: rs5746220
Type: single nucleotide variant
Location: chr3:12600219 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 308: the 'disordered' region; a UniProt-annotated variant site (in)

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

Also linked: Noonan syndrome 5 LEOPARD syndrome 2 Noonan syndrome and Noonan-related syndrome

Similar variants

RAF1 p.Pro308= Likely benign ★★ same residue
RAF1 p.Pro308Ser Uncertain significance ★ ⚠ 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

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-pro308leu (accessed [today's date]).

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