Is ARB2A p.Arg241His (c.722G>A) pathogenic?

ARB2A p.Arg241His (c.722G>A) is classified Uncertain significance in ARB2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-04). AlphaMissense: likely benign (0.2709); Very rare (popmax 0.00224%, eas).

How common is ARB2A p.Arg241His (c.722G>A) in the general population?

ARB2A p.Arg241His (c.722G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about ARB2A p.Arg241His (c.722G>A)?

AlphaMissense predicts likely benign (score 0.2709) — an in-silico prediction, not a clinical call.

ARB2A p.Arg241His

c.722G>A · VCV3419980

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2709	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -7.96	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 4.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 454 kb · p 0.66 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,680 alleles

Filtering AF 0.00146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00192% 31/1,610,928 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00481%	20,780
East Asiangrpmax	0.00224%	44,680
South Asian	0.0022%	45,497
European (non-Finnish)	0.00212%	47,118

Remaining individuals 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: ARB2A
Protein: p.Arg241His
Coding: c.722G>A
MANE Select: NM_032042
Type: single nucleotide variant
Location: chr5:93881534 (GRCh38)
Structure: AlphaFold pLDDT 84.01
Residue 241: the 'disordered' region

Full ARB2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARB2A p.Arg241Cys Uncertain significance ★ ⚠ same residue
ARB2A p.Ala271Val Uncertain significance ★ ⚠ same type
ARB2A p.Ala283Val Uncertain significance ★ ⚠ same type
ARB2A p.Arg227Gly Uncertain significance ★ ⚠ same type
ARB2A p.Arg227Trp Uncertain significance ★ ⚠ same type
ARB2A p.Arg240Gln Uncertain significance ★ ⚠ same type
ARB2A p.Arg306Gln Uncertain significance ★ ⚠ same type
ARB2A p.Asn146Asp 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/arb2a-p-arg241his (accessed [today's date]).

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