Is RAF1 p.Leu538Ser (c.1613T>C) pathogenic?

RAF1 p.Leu538Ser (c.1613T>C) is classified Uncertain significance in RAF1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-05). AlphaMissense: likely pathogenic (0.9429); Very rare (popmax 0.00833%, amr); Associated with Cardiovascular phenotype.

What condition is associated with RAF1 p.Leu538Ser (c.1613T>C)?

RAF1 p.Leu538Ser (c.1613T>C) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is RAF1 p.Leu538Ser (c.1613T>C) in the general population?

RAF1 p.Leu538Ser (c.1613T>C) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about RAF1 p.Leu538Ser (c.1613T>C)?

AlphaMissense predicts likely pathogenic (score 0.9429) — an in-silico prediction, not a clinical call.

RAF1 p.Leu538Ser

c.1613T>C · rs730881011 · VCV864526

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9429 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9429	likely pathogenic
REVEL	0.881	moderately pathogenic-leaning
SaProt	LLR -14.41	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00833% Admixed American · 5/60,018 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.00041% 6/1,461,892 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,004
European (non-Finnish)	8.47e-05%	1,180,032

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.Leu538Ser
Coding: c.1613T>C
MANE Select: NM_002880
dbSNP: rs730881011
Type: single nucleotide variant
Location: chr3:12585177 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 538: 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: RASopathy

Similar variants

RAF1 p.Leu538= Likely benign ★★ same residue
RAF1 p.Leu538Ter 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-leu538ser (accessed [today's date]).

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