Is ABCA2 p.Arg99His (c.296G>A) pathogenic?

ABCA2 p.Arg99His (c.296G>A) is classified Uncertain significance in ABCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-04). AlphaMissense: likely benign (0.1027); Very rare (popmax 0.00896%, amr).

How common is ABCA2 p.Arg99His (c.296G>A) in the general population?

ABCA2 p.Arg99His (c.296G>A) is very rare (popmax 0.00896%, amr) (gnomAD).

What do computational predictors say about ABCA2 p.Arg99His (c.296G>A)?

AlphaMissense predicts likely benign (score 0.1027) — an in-silico prediction, not a clinical call.

ABCA2 p.Arg99His

c.296G>A · VCV3511112

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1027 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00896%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1027	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -6.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 5,362 bp · p 3.2e-05 · regional, not allelic
Overall
CADD	20.8	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R98H vs ClinVar R99H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00896% Admixed American · 5/55,776 alleles

Filtering AF 0.00345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0022%

Overall 0.00133% 21/1,583,522 alleles · very rare exomes 20/1,432,556 · genomes 1/150,966 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00896%	11,155
East Asian	0.00229%	43,582
European (non-Finnish)	0.00129%	77,709

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: ABCA2
Protein: p.Arg99His
Coding: c.296G>A
MANE Select: NM_001606
Type: single nucleotide variant
Location: chr9:137022845 (GRCh38)
Gene constraint: LOEUF 0.436 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.46

Full ABCA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCA2 p.Arg99= Likely benign ★ same residue
ABCA2 p.Gln1370Ter Likely pathogenic ★★ same type
ABCA2 c.3883-3C>T Uncertain significance ★★ same type
ABCA2 p.Ala1357Thr Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala1620Thr Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala1645Val Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala1715Ser Uncertain significance ★★ ⚠ same type
ABCA2 p.Ala2180Thr 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/abca2-p-arg99his (accessed [today's date]).

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