Is ARAP1 p.Arg422His (c.1265G>A) pathogenic?

ARAP1 p.Arg422His (c.1265G>A) is classified Likely benign in ARAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-01). AlphaMissense: likely benign (0.0873); Rare (popmax 0.653%, nfe).

How common is ARAP1 p.Arg422His (c.1265G>A) in the general population?

ARAP1 p.Arg422His (c.1265G>A) is rare (popmax 0.653%, nfe) (gnomAD).

What do computational predictors say about ARAP1 p.Arg422His (c.1265G>A)?

AlphaMissense predicts likely benign (score 0.0873) — an in-silico prediction, not a clinical call.

ARAP1 p.Arg422His

c.1265G>A · rs148377320 · VCV2642129

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0873 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.653%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0873	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -8.74	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 0.23	GERP 0.83, phastCons 0.009
Regional constraint	o/e 0.80	unconstrained · MANE · 15 kb · p 7.9e-09 · regional, not allelic
Overall
CADD	18.14	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 0.653% European (non-Finnish) · 7,705/1,179,962 alleles

Filtering AF 0.641% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.636%

Overall 0.591% 9,538/1,612,802 alleles · rare exomes 8,717/1,460,538 · genomes 821/152,264 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.8%	56
Ashkenazi Jewishnot grpmax-eligible	0.912%	110
European (non-Finnish)grpmax	0.653%	153
Remaining individualsnot grpmax-eligible	0.472%	212
Admixed American	0.105%	953
African / African-American	0.0706%	1,416
Middle Eastern	0.033%	3,031
South Asian	0.0198%	5,060
East Asian	0.00223%	44,864

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: ARAP1
Protein: p.Arg422His
Coding: c.1265G>A
MANE Select: NM_001040118
dbSNP: rs148377320
Type: single nucleotide variant
Location: chr11:72710536 (GRCh38)
Gene constraint: LOEUF 0.572 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.81 · 1 PDB

Full ARAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARAP1 p.Gln1047Glu Benign ★★ same type
ARAP1 p.Pro1039= Benign ★★ same type
ARAP1 p.Pro254Leu Benign ★★ same type
ARAP1 p.Val1408Met Benign ★★ same type
ARAP1 p.Ala1046Ser Uncertain significance ★ ⚠ same type
ARAP1 p.Ala1124Thr Uncertain significance ★ ⚠ same type
ARAP1 p.Ala1199Thr Uncertain significance ★ ⚠ same type
ARAP1 p.Ala1389Thr 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/arap1-p-arg422his (accessed [today's date]).

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