Is RAF1 p.Asp633= (c.1899T>C) pathogenic?

RAF1 p.Asp633= (c.1899T>C) is classified Likely benign in RAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). Very rare (popmax 0.000424%, nfe); Associated with RASopathy.

What condition is associated with RAF1 p.Asp633= (c.1899T>C)?

RAF1 p.Asp633= (c.1899T>C) is associated with RASopathy (ClinVar).

How common is RAF1 p.Asp633= (c.1899T>C) in the general population?

RAF1 p.Asp633= (c.1899T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

RAF1 p.Asp633=

c.1899T>C · rs1286582905 · VCV742213

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

RASopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.025	GERP -5.5, phastCons 0.29
Overall
CADD	2.112	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,020 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,146 alleles · very rare exomes 5/1,461,890 · genomes 0/152,256 · 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.Asp633=
Coding: c.1899T>C
MANE Select: NM_002880
dbSNP: rs1286582905
Type: single nucleotide variant
Location: chr3:12584562 (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.Asp633Ala Uncertain significance ★★ same residue
RAF1 p.Asp633Gly Uncertain significance ★ same residue
RAF1 p.Asp633Asn 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

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-asp633 (accessed [today's date]).

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