Is ARB2A p.Glu99Lys (c.295G>A) pathogenic?

ARB2A p.Glu99Lys (c.295G>A) is classified Uncertain significance in ARB2A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-11). AlphaMissense: likely pathogenic (0.9966); Very rare (popmax 0.0011%, nfe).

How common is ARB2A p.Glu99Lys (c.295G>A) in the general population?

ARB2A p.Glu99Lys (c.295G>A) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about ARB2A p.Glu99Lys (c.295G>A)?

AlphaMissense predicts likely pathogenic (score 0.9966) — an in-silico prediction, not a clinical call.

ARB2A p.Glu99Lys

c.295G>A · rs745330544 · VCV2289057

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9966 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9966	likely pathogenic · top 8% in ARB2A
REVEL	0.367	indeterminate
SaProt	LLR -12.20	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 454 kb · p 0.66 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0011% European (non-Finnish) · 13/1,177,722 alleles

Filtering AF 0.000616% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000475%

Overall 0.00081% 13/1,604,908 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: ARB2A
Protein: p.Glu99Lys
Coding: c.295G>A
MANE Select: NM_032042
dbSNP: rs745330544
Type: single nucleotide variant
Location: chr5:94050745 (GRCh38)
Structure: AlphaFold pLDDT 84.01

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

Similar variants

POU5F2 p.Ala99Ser 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.Arg241Cys Uncertain significance ★ ⚠ same type
ARB2A p.Arg241His 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-glu99lys (accessed [today's date]).

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