Is ABCA2 p.Arg954His (c.2861G>A) pathogenic?

ABCA2 p.Arg954His (c.2861G>A) is classified Uncertain significance in ABCA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-04). AlphaMissense: likely benign (0.072); Very rare (popmax 0.00267%, afr); Associated with intellectual developmental disorder with poor growth and with or without seizures or ataxia.

How common is ABCA2 p.Arg954His (c.2861G>A) in the general population?

ABCA2 p.Arg954His (c.2861G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ABCA2 p.Arg954His (c.2861G>A)?

AlphaMissense predicts likely benign (score 0.072) — an in-silico prediction, not a clinical call.

ABCA2 p.Arg954His

Q: What condition is associated with ABCA2 p.Arg954His (c.2861G>A)?

ABCA2 p.Arg954His (c.2861G>A) is associated with intellectual developmental disorder with poor growth and with or without seizures or ataxia (ClinVar).

c.2861G>A · rs762702619 · VCV3067860

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.072 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual developmental disorder with poor growth and with or without seizures or ataxia

Computational evidence

Protein change
AlphaMissense	0.072	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -8.62	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 -1.3	GERP -1.4
Regional constraint	o/e 0.88	unconstrained · MANE · 609 bp · p 0.15 · regional, not allelic
Overall
CADD	11.7	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 R953H vs ClinVar R954H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,006 alleles

Filtering AF 0.000501% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.0011% 16/1,457,740 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,503
East Asian	0.00223%	44,850
Finnishnot grpmax-eligible	0.00162%	61,858
South Asian	0.0011%	90,890
European (non-Finnish)	0.000933%	107,169

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.Arg954His
Coding: c.2861G>A
MANE Select: NM_001606
dbSNP: rs762702619
Type: single nucleotide variant
Location: chr9:137016636 (GRCh38)
Gene constraint: LOEUF 0.436 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.46
Residue 954: a UniProt-annotated variant site (in idpogsa)

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

Disease context

intellectual developmental disorder with poor growth and with or without seizures or ataxia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCA2 p.Arg954Cys Uncertain significance ★★ ⚠ same residue
ABCA2 p.Gln1370Ter Likely pathogenic ★★ same condition
ABCA2 p.Ala367Thr Uncertain significance ★★ ⚠ same condition
ABCA2 p.Arg114Gln Uncertain significance ★★ ⚠ same condition
ABCA2 p.Arg1160His Uncertain significance ★★ ⚠ same condition
ABCA2 p.Arg1383His Uncertain significance ★★ ⚠ same condition
ABCA2 p.Arg1664Trp Uncertain significance ★★ ⚠ same condition
ABCA2 p.Asn1755Lys Uncertain significance ★★ ⚠ same condition

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-arg954his (accessed [today's date]).

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