Is RAF1 p.Asp381Asn (c.1141G>A) pathogenic?

RAF1 p.Asp381Asn (c.1141G>A) is classified Benign in RAF1 (ClinVar, Expert panel, 8 submitters; last evaluated 2017-04-18). AlphaMissense: likely benign (0.096); Rare (popmax 0.253%, sas); Associated with RASopathy.

What condition is associated with RAF1 p.Asp381Asn (c.1141G>A)?

RAF1 p.Asp381Asn (c.1141G>A) is associated with RASopathy, Noonan syndrome with multiple lentigines, Noonan syndrome (ClinVar).

How common is RAF1 p.Asp381Asn (c.1141G>A) in the general population?

RAF1 p.Asp381Asn (c.1141G>A) is rare (popmax 0.253%, sas) (gnomAD).

What do computational predictors say about RAF1 p.Asp381Asn (c.1141G>A)?

AlphaMissense predicts likely benign (score 0.096) — an in-silico prediction, not a clinical call.

RAF1 p.Asp381Asn

c.1141G>A · rs559632360 · VCV181509

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.096 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.253%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.1141G>A (p.Asp381Asn) variant in the RAF1 gene is 0.162% (36/16508) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.096	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -5.74	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 2.2	GERP -2.3, phastCons 0.98
Overall
CADD	16.27	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 0.253% South Asian · 230/91,082 alleles

Filtering AF 0.226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.215%

Overall 0.0154% 249/1,614,126 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.253%	396
Remaining individualsnot grpmax-eligible	0.0112%	8,929
Admixed American	0.00167%	60,020
European (non-Finnish)	0.000932%	107,274

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.Asp381Asn
Coding: c.1141G>A
MANE Select: NM_002880
dbSNP: rs559632360
Type: single nucleotide variant
Location: chr3:12591760 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 68.24 · 76 PDB
Residue 381: the protein kinase domain

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

Also linked: Noonan syndrome with multiple lentigines Noonan syndrome Noonan syndrome and Noonan-related syndrome

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.Ser257Pro Likely pathogenic ★★★ ⚠ same condition
RAF1 p.Ser259Ala Pathogenic ★★★ ⚠ same condition
RAF1 p.Ser259Thr 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-asp381asn (accessed [today's date]).

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