Is ARHGAP40 p.Pro28Leu (c.83C>T) pathogenic?

ARHGAP40 p.Pro28Leu (c.83C>T) is classified Uncertain significance in ARHGAP40 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-16). Very rare (popmax 0.0023%, amr).

How common is ARHGAP40 p.Pro28Leu (c.83C>T) in the general population?

ARHGAP40 p.Pro28Leu (c.83C>T) is very rare (popmax 0.0023%, amr) (gnomAD).

ARHGAP40 p.Pro28Leu

c.83C>T · VCV3312344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0023%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP 1, phastCons 0.018
Regional constraint	o/e 0.85	unconstrained · MANE · 48 kb · p 1.3e-05 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0023% Admixed American · 1/43,530 alleles

Overall 0.000176% 2/1,135,164 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0023%	43,530
South Asian	0.00124%	80,860

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: ARHGAP40
Protein: p.Pro28Leu
Coding: c.83C>T
MANE Select: NM_001164431
Type: single nucleotide variant
Location: chr20:38602025 (GRCh38)
Gene constraint: LOEUF 0.718 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.96

Full ARHGAP40 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP40 p.Ala153Val Uncertain significance ★ ⚠ same type
ARHGAP40 p.Ala200Asp Uncertain significance ★ ⚠ same type
ARHGAP40 p.Ala227Asp Uncertain significance ★ ⚠ same type
ARHGAP40 p.Ala233Val Uncertain significance ★ same type
ARHGAP40 p.Ala296Val Uncertain significance ★ same type
ARHGAP40 p.Ala385Gly Uncertain significance ★ ⚠ same type
ARHGAP40 p.Ala398Thr Uncertain significance ★ ⚠ same type
ARHGAP40 p.Ala423Thr Uncertain significance ★ ⚠ 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/arhgap40-p-pro28leu (accessed [today's date]).

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