Is RAF1 p.Gln504Pro (c.1511A>C) pathogenic?

RAF1 p.Gln504Pro (c.1511A>C) is classified Uncertain significance in RAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-07). AlphaMissense: likely pathogenic (0.7531); Ultra-rare (popmax 0.0165%, mid); Associated with Noonan syndrome 5.

What condition is associated with RAF1 p.Gln504Pro (c.1511A>C)?

RAF1 p.Gln504Pro (c.1511A>C) is associated with Noonan syndrome 5 (ClinVar).

How common is RAF1 p.Gln504Pro (c.1511A>C) in the general population?

RAF1 p.Gln504Pro (c.1511A>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about RAF1 p.Gln504Pro (c.1511A>C)?

AlphaMissense predicts likely pathogenic (score 0.7531) — an in-silico prediction, not a clinical call.

RAF1 p.Gln504Pro

c.1511A>C · VCV4293995

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7531 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Noonan syndrome 5

Computational evidence

Protein change
AlphaMissense	0.7531	likely pathogenic
REVEL	0.818	moderately pathogenic-leaning
SaProt	LLR -9.85	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 7.9	GERP 2.8, phastCons 1
Overall
CADD	28.8	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 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00423%

Overall 0.00471% 76/1,612,350 alleles · ultra-rare exomes 75/1,460,028 · genomes 1/152,322 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
European (non-Finnish)	0.00577%	17,329
Remaining individualsnot grpmax-eligible	0.0048%	20,814
East Asian	0.00446%	22,435
African / African-American	0.00133%	75,012
South Asian	0.0011%	91,044

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.Gln504Pro
Coding: c.1511A>C
MANE Select: NM_002880
Type: single nucleotide variant
Location: chr3:12585706 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 504: the protein kinase domain

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

Disease context

Noonan syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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.Ser259Ala Pathogenic ★★★ ⚠ same condition
RAF1 p.Ser259Tyr Pathogenic ★★★ same condition
RAF1 p.Arg398Leu Uncertain significance ★★★ ⚠ 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-gln504pro (accessed [today's date]).

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