Is RASA1 p.Pro649Ala (c.1945C>G) pathogenic?

RASA1 p.Pro649Ala (c.1945C>G) is classified Uncertain significance in RASA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-19). AlphaMissense: likely benign (0.048); Very rare (popmax 0.00187%, nfe); Associated with capillary malformation-arteriovenous malformation syndrome.

What condition is associated with RASA1 p.Pro649Ala (c.1945C>G)?

RASA1 p.Pro649Ala (c.1945C>G) is associated with capillary malformation-arteriovenous malformation syndrome (ClinVar).

How common is RASA1 p.Pro649Ala (c.1945C>G) in the general population?

RASA1 p.Pro649Ala (c.1945C>G) is very rare (popmax 0.00187%, nfe) (gnomAD).

What do computational predictors say about RASA1 p.Pro649Ala (c.1945C>G)?

AlphaMissense predicts likely benign (score 0.048) — an in-silico prediction, not a clinical call.

RASA1 p.Pro649Ala

c.1945C>G · VCV3707329

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.048 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00187%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

capillary malformation-arteriovenous malformation syndrome

Computational evidence

Protein change
AlphaMissense	0.048	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -7.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 18 kb · p 2.3e-14 · regional, not allelic
Overall
CADD	22.4	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

Grpmax group 0.00187% European (non-Finnish) · 22/1,177,354 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00137% 22/1,608,798 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: RASA1
Protein: p.Pro649Ala
Coding: c.1945C>G
MANE Select: NM_001239 · reported on NM_002890
Type: single nucleotide variant
Location: chr5:87374850 (GRCh38)

Full RASA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

capillary malformation-arteriovenous malformation syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/rasa1-p-pro649ala (accessed [today's date]).

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