Is ABCA2 p.Arg2156His (c.6467G>A) pathogenic?

ABCA2 p.Arg2156His (c.6467G>A) is classified Uncertain significance in ABCA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-24). AlphaMissense: ambiguous (0.5469); Ultra-rare (popmax 0.012%, amr).

How common is ABCA2 p.Arg2156His (c.6467G>A) in the general population?

ABCA2 p.Arg2156His (c.6467G>A) is ultra-rare (popmax 0.012%, amr) (gnomAD).

What do computational predictors say about ABCA2 p.Arg2156His (c.6467G>A)?

AlphaMissense predicts ambiguous (score 0.5469) — an in-silico prediction, not a clinical call.

ABCA2 p.Arg2156His

c.6467G>A · rs367589587 · VCV2408762

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5469 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5469	ambiguous
REVEL	0.765	pathogenic-leaning
SaProt	LLR -11.62	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 0.59, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 3,800 bp · p 6.1e-23 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R2155H vs ClinVar R2156H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% Admixed American · 7/58,426 alleles

Filtering AF 0.00556% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00414%

Overall 0.00513% 82/1,598,240 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.012%	8,347
Remaining individualsnot grpmax-eligible	0.0113%	8,830
European (non-Finnish)	0.00562%	17,786
African / African-American	0.00268%	37,285

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.Arg2156His
Coding: c.6467G>A
MANE Select: NM_001606
dbSNP: rs367589587
Type: single nucleotide variant
Location: chr9:137010011 (GRCh38)
Gene constraint: LOEUF 0.436 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.46
Residue 2156: the abc transporter 2 domain; a UniProt-annotated variant site (in idpogsa)

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

Similar variants

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
ABCA2 p.Ala2206Val 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-arg2156his (accessed [today's date]).

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