Is ARAP3 p.Phe25Leu (c.75C>G) pathogenic?

ARAP3 p.Phe25Leu (c.75C>G) is classified Uncertain significance in ARAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-10). AlphaMissense: likely pathogenic (0.9711); Very rare (popmax 0.00266%, afr).

How common is ARAP3 p.Phe25Leu (c.75C>G) in the general population?

ARAP3 p.Phe25Leu (c.75C>G) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about ARAP3 p.Phe25Leu (c.75C>G)?

AlphaMissense predicts likely pathogenic (score 0.9711) — an in-silico prediction, not a clinical call.

ARAP3 p.Phe25Leu

c.75C>G · rs2099912797 · VCV2325948

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9711 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9711	likely pathogenic · top 9% in ARAP3
REVEL	0.826	moderately pathogenic-leaning
SaProt	LLR -7.88	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 8,347 bp · p 0.061 · regional, not allelic
Overall
CADD	24.4	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 0.00266% African / African-American · 2/75,072 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000137% 2/1,461,234 alleles · very rare

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: ARAP3
Protein: p.Phe25Leu
Coding: c.75C>G
MANE Select: NM_022481
dbSNP: rs2099912797
Type: single nucleotide variant
Location: chr5:141680412 (GRCh38)
Gene constraint: LOEUF 0.598 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.20 · 7 PDB
Residue 25: the sam domain; an α-helix

Full ARAP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARAP3 p.Ala1045Val Uncertain significance ★ ⚠ same type
ARAP3 p.Ala10Thr Uncertain significance ★ ⚠ same type
ARAP3 p.Ala1159Val Uncertain significance ★ ⚠ same type
ARAP3 p.Ala1276Ser Uncertain significance ★ ⚠ same type
ARAP3 p.Ala1342Thr Uncertain significance ★ ⚠ same type
ARAP3 p.Ala216Asp Uncertain significance ★ ⚠ same type
ARAP3 p.Ala22Val Uncertain significance ★ ⚠ same type
ARAP3 p.Ala36Thr 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/arap3-p-phe25leu (accessed [today's date]).

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