Is ARHGAP21 p.Pro341Thr (c.1021C>A) pathogenic?

ARHGAP21 p.Pro341Thr (c.1021C>A) is classified Uncertain significance in ARHGAP21 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely benign (0.0714); Very rare (popmax 0.00223%, eas).

How common is ARHGAP21 p.Pro341Thr (c.1021C>A) in the general population?

ARHGAP21 p.Pro341Thr (c.1021C>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ARHGAP21 p.Pro341Thr (c.1021C>A)?

AlphaMissense predicts likely benign (score 0.0714) — an in-silico prediction, not a clinical call.

ARHGAP21 p.Pro341Thr

c.1021C>A · rs768578438 · VCV2215012

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0714 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0714	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	LLR -6.19	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 0.029	GERP -4.4
Regional constraint	o/e 0.79	unconstrained · MANE · 125 kb · p 7.3e-15 · regional, not allelic
Overall
CADD	2.543	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 0.00223% East Asian · 1/44,888 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00031% 5/1,613,816 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,888
African / African-American	0.00133%	74,914
South Asian	0.0011%	91,072
European (non-Finnish)	0.00017%	589,936

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: ARHGAP21
Protein: p.Pro341Thr
Coding: c.1021C>A
MANE Select: NM_020824
dbSNP: rs768578438
Type: single nucleotide variant
Location: chr10:24620874 (GRCh38)
Gene constraint: LOEUF 0.261 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 45.03 · 3 PDB

Full ARHGAP21 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP10 p.Glu341Lys Uncertain significance ★ ⚠ same residue
ARHGAP21 p.Pro341Ala Uncertain significance ★ ⚠ same residue
ARHGAP10 p.Asn222Ser Uncertain significance ★★ ⚠ same type
ARHGAP10 p.Ala405= Benign ★★ same type
ARHGAP10 p.Arg243= Benign ★★ same type
ARHGAP10 p.Ile676Val Likely benign ★★ same type
ARHGAP10 p.Ser487= Benign ★★ same type
ARHGAP10 p.Tyr614= Benign ★★ same type

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/arhgap21-p-pro341thr (accessed [today's date]).

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