Is ARHGAP45 p.Pro435Leu (c.1304C>T) pathogenic?

ARHGAP45 p.Pro435Leu (c.1304C>T) is classified Likely benign in ARHGAP45 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-27). AlphaMissense: likely benign (0.0769); Very rare (popmax 0.0041%, afr).

How common is ARHGAP45 p.Pro435Leu (c.1304C>T) in the general population?

ARHGAP45 p.Pro435Leu (c.1304C>T) is very rare (popmax 0.0041%, afr) (gnomAD).

What do computational predictors say about ARHGAP45 p.Pro435Leu (c.1304C>T)?

AlphaMissense predicts likely benign (score 0.0769) — an in-silico prediction, not a clinical call.

ARHGAP45 p.Pro435Leu

c.1304C>T · rs758250463 · VCV2219149

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0769 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0041%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0769	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -8.54	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 2.3	GERP -1.2, phastCons 0.3
Regional constraint	o/e 1.06	unconstrained · MANE · 12 kb · p 0.048 · regional, not allelic
Overall
CADD	16.6	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

Grpmax group 0.0041% African / African-American · 3/73,144 alleles

Filtering AF 0.00109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000502%

Overall 0.0018% 28/1,553,256 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0251%	3,983
African / African-Americangrpmax	0.0041%	24,381
Remaining individualsnot grpmax-eligible	0.00332%	30,080
South Asian	0.00238%	42,086
European (non-Finnish)	0.000523%	191,330

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ARHGAP45
Protein: p.Pro435Leu
Coding: c.1304C>T
MANE Select: NM_012292
dbSNP: rs758250463
Type: single nucleotide variant
Location: chr19:1077975 (GRCh38)
Gene constraint: LOEUF 0.75 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.96 · 2 PDB
Residue 435: the f-bar domain

Full ARHGAP45 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARHGAP45 c.422-1836C>T Benign ★★ same type
ARHGAP45 p.Ala426Val Benign ★★ ⚠ same type
ARHGAP45 p.Arg139His Benign ★★ same type
ARHGAP45 p.Glu1090Gly Benign ★★ same type
ARHGAP45 p.Gly1019Arg Likely benign ★★ same type
ARHGAP45 p.Leu138= Benign ★★ same type
ARHGAP45 p.Pro1011= Benign ★★ same type
ARHGAP45 p.Ser1032= 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/arhgap45-p-pro435leu (accessed [today's date]).

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