Is RASA1 p.Pro440Ser (c.1318C>T) pathogenic?

RASA1 p.Pro440Ser (c.1318C>T) is classified Uncertain significance in RASA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely pathogenic (0.586); Absent from gnomAD v4.1; Associated with capillary malformation-arteriovenous malformation syndrome.

What condition is associated with RASA1 p.Pro440Ser (c.1318C>T)?

RASA1 p.Pro440Ser (c.1318C>T) is associated with capillary malformation-arteriovenous malformation syndrome (ClinVar).

How common is RASA1 p.Pro440Ser (c.1318C>T) in the general population?

RASA1 p.Pro440Ser (c.1318C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RASA1 p.Pro440Ser (c.1318C>T)?

AlphaMissense predicts likely pathogenic (score 0.586) — an in-silico prediction, not a clinical call.

RASA1 p.Pro440Ser

c.1318C>T · VCV4753506

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.586 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

capillary malformation-arteriovenous malformation syndrome

Computational evidence

Protein change
AlphaMissense	0.586	likely pathogenic
REVEL	0.729	pathogenic-leaning
SaProt	LLR -6.84	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 4	GERP 1.1, phastCons 1
Regional constraint	o/e 1.33	unconstrained · MANE · 9,360 bp · p 0.16 · regional, not allelic
Overall
CADD	23.3	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

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.Pro440Ser
Coding: c.1318C>T
MANE Select: NM_002890
Type: single nucleotide variant
Location: chr5:87353221 (GRCh38)
Gene constraint: LOEUF 0.3 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.37 · 15 PDB
Residue 440: the sh2 2 domain

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.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
RASA1 p.Ala40Ser Uncertain significance ★★ ⚠ same condition
RASA1 p.Ala40Thr 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-pro440ser (accessed [today's date]).

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