Is RASA1 p.Pro138Ala (c.412C>G) pathogenic?

RASA1 p.Pro138Ala (c.412C>G) is classified Uncertain significance in RASA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-02). AlphaMissense: likely benign (0.1046); Absent from gnomAD v4.1; Associated with capillary malformation-arteriovenous malformation syndrome.

What condition is associated with RASA1 p.Pro138Ala (c.412C>G)?

RASA1 p.Pro138Ala (c.412C>G) is associated with capillary malformation-arteriovenous malformation syndrome (ClinVar).

How common is RASA1 p.Pro138Ala (c.412C>G) in the general population?

RASA1 p.Pro138Ala (c.412C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RASA1 p.Pro138Ala (c.412C>G)?

AlphaMissense predicts likely benign (score 0.1046) — an in-silico prediction, not a clinical call.

RASA1 p.Pro138Ala

c.412C>G · rs775315018 · VCV1693899

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1046 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

capillary malformation-arteriovenous malformation syndrome

Computational evidence

Protein change
AlphaMissense	0.1046	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -7.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP -0.36, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 63 kb · p 0.0025 · regional, not allelic
Overall
CADD	21.2	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: RASA1
Protein: p.Pro138Ala
Coding: c.412C>G
MANE Select: NM_002890
dbSNP: rs775315018
Type: single nucleotide variant
Location: chr5:87268863 (GRCh38)
Gene constraint: LOEUF 0.3 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.37 · 15 PDB

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

Similar variants

RASA1 p.Pro138Ser Uncertain significance ★★ ⚠ same residue
RASA1 p.Pro138= Likely benign ★ same residue
RASA1 p.Ala115Gly Uncertain significance ★★ ⚠ same condition
RASA1 p.Ala115Val Uncertain significance ★★ ⚠ same condition
RASA1 p.Ala125Gly Uncertain significance ★★ ⚠ same condition
RASA1 p.Ala23Thr Uncertain significance ★★ ⚠ same condition
RASA1 p.Ala29Val Uncertain significance ★★ ⚠ same condition
RASA1 p.Ala32Val 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/rasa1-p-pro138ala (accessed [today's date]).

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