Is RAF1 p.Pro505Arg (c.1514C>G) pathogenic?

RAF1 p.Pro505Arg (c.1514C>G) is classified Uncertain significance in RAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-16). AlphaMissense: likely pathogenic (0.984); Very rare (popmax 8.48e-05%, nfe).

How common is RAF1 p.Pro505Arg (c.1514C>G) in the general population?

RAF1 p.Pro505Arg (c.1514C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about RAF1 p.Pro505Arg (c.1514C>G)?

AlphaMissense predicts likely pathogenic (score 0.984) — an in-silico prediction, not a clinical call.

RAF1 p.Pro505Arg

c.1514C>G · VCV4851752

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.984	likely pathogenic
REVEL	0.785	moderately pathogenic-leaning
SaProt	LLR -9.63	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
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	29.3	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 8.48e-05% European (non-Finnish) · 1/1,179,764 alleles

Overall 6.84e-05% 1/1,461,556 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.Pro505Arg
Coding: c.1514C>G
MANE Select: NM_002880
Type: single nucleotide variant
Location: chr3:12585703 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 505: the protein kinase domain

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

Similar variants

RAF1 p.Pro505Ser Uncertain significance ★★ ⚠ same residue
RAF1 p.Pro505= Likely benign ★★ same residue
RAF1 p.Pro505Thr Uncertain significance ★ ⚠ same residue
RAF1 p.Arg256Ser Likely pathogenic ★★★ ⚠ same type
RAF1 p.Gly361Ala Pathogenic ★★★ ⚠ same type
RAF1 p.Leu613Val Pathogenic ★★★ same type
RAF1 p.Pro261Ser Pathogenic ★★★ ⚠ same type
RAF1 p.Ser257Leu Pathogenic ★★★ ⚠ same type

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-pro505arg (accessed [today's date]).

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