Is RASA2 p.Ser666Arg (c.1996A>C) pathogenic?

RASA2 p.Ser666Arg (c.1996A>C) is classified Uncertain significance in RASA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-01). Very rare (popmax 0.00539%, afr); Associated with RASA2-related disorder.

What condition is associated with RASA2 p.Ser666Arg (c.1996A>C)?

RASA2 p.Ser666Arg (c.1996A>C) is associated with RASA2-related disorder (ClinVar).

How common is RASA2 p.Ser666Arg (c.1996A>C) in the general population?

RASA2 p.Ser666Arg (c.1996A>C) is very rare (popmax 0.00539%, afr) (gnomAD).

RASA2 p.Ser666Arg

c.1996A>C · rs372126702 · VCV1784049

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00539%, afr)

Conditions

RASA2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.329	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 0.64, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 121 kb · p 0.039 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00539% African / African-American · 4/74,150 alleles

Filtering AF 0.00176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00105%

Overall 0.00025% 4/1,597,130 alleles · very rare exomes 0/1,444,950 · genomes 4/152,180 · joint denominator

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: RASA2
Protein: p.Ser666Arg
Coding: c.1996A>C
MANE Select: NM_006506
dbSNP: rs372126702
Type: single nucleotide variant
Location: chr3:141607740 (GRCh38)
Gene constraint: LOEUF 1.484 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.63
Residue 666: the ph domain

Full RASA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

RASA2-related disorder

Similar variants

RASA2 p.Ser666Gly Uncertain significance ★ same residue
RASA2 p.Val660Met Uncertain significance ★★ same condition
RASA2 c.611+1G>T Uncertain significance ★ same condition
RASA2 p.Ala380Thr Uncertain significance ★ same condition
RASA2 p.Asn146Lys Uncertain significance ★ same condition
RASA2 p.Asn277Lys Conflicting classifications of pathogenicity ★ same condition
RASA2 p.Trp137Arg Uncertain significance ★ same condition
RASA2 p.Val517Leu Conflicting classifications of pathogenicity ★ 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/rasa2-p-ser666arg (accessed [today's date]).

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