Is ARAP2 p.Arg642Leu (c.1925G>T) pathogenic?

ARAP2 p.Arg642Leu (c.1925G>T) is classified Uncertain significance in ARAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely pathogenic (0.7379); Ultra-rare (popmax 0.0152%, amr).

How common is ARAP2 p.Arg642Leu (c.1925G>T) in the general population?

ARAP2 p.Arg642Leu (c.1925G>T) is ultra-rare (popmax 0.0152%, amr) (gnomAD).

What do computational predictors say about ARAP2 p.Arg642Leu (c.1925G>T)?

AlphaMissense predicts likely pathogenic (score 0.7379) — an in-silico prediction, not a clinical call.

ARAP2 p.Arg642Leu

c.1925G>T · VCV4641941

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7379 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0152%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7379	likely pathogenic
REVEL	0.149	moderately benign-leaning
SaProt	LLR -6.18	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 162 kb · p 0.0019 · regional, not allelic
Overall
CADD	22.6	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 0.0152% Admixed American · 9/59,042 alleles

Filtering AF 0.00795% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00587%

Overall 0.000746% 12/1,608,730 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0152%	6,560
Remaining individualsnot grpmax-eligible	0.00321%	31,134
European (non-Finnish)	8.49e-05%	1,178,037

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: ARAP2
Protein: p.Arg642Leu
Coding: c.1925G>T
MANE Select: NM_015230
Type: single nucleotide variant
Location: chr4:36166980 (GRCh38)
Gene constraint: LOEUF 0.884 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.42 · 2 PDB
Residue 642: the ph 2 domain

Full ARAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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ARAP2 p.Ala1261Val Uncertain significance ★ ⚠ same type
ARAP2 p.Ala1353Glu Uncertain significance ★ ⚠ same type
ARAP2 p.Ala1375Pro Uncertain significance ★ ⚠ same type
ARAP2 p.Ala1421Ser Uncertain significance ★ ⚠ same type
ARAP2 p.Ala1421Thr Uncertain significance ★ ⚠ same type
ARAP2 p.Ala1508Thr 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/arap2-p-arg642leu (accessed [today's date]).

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