Is RAF1 p.Ser243Pro (c.727T>C) pathogenic?

RAF1 p.Ser243Pro (c.727T>C) is classified Uncertain significance in RAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-18). AlphaMissense: likely benign (0.0634); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with RAF1 p.Ser243Pro (c.727T>C)?

RAF1 p.Ser243Pro (c.727T>C) is associated with RASopathy (ClinVar).

How common is RAF1 p.Ser243Pro (c.727T>C) in the general population?

RAF1 p.Ser243Pro (c.727T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RAF1 p.Ser243Pro (c.727T>C)?

AlphaMissense predicts likely benign (score 0.0634) — an in-silico prediction, not a clinical call.

RAF1 p.Ser243Pro

c.727T>C · rs2125398286 · VCV2838936

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0634 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.0634	likely benign
REVEL	0.279	benign-leaning
SaProt	LLR -6.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 0.5, phastCons 1
Overall
CADD	16.08	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RAF1
Protein: p.Ser243Pro
Coding: c.727T>C
MANE Select: NM_002880
dbSNP: rs2125398286
Type: single nucleotide variant
Location: chr3:12604243 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 243: the 'disordered' region

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.Ser243Cys 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
RAF1 p.Ser259Ala 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-ser243pro (accessed [today's date]).

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