Is ABCA2 p.Leu2076Val (c.6226C>G) pathogenic?

ABCA2 p.Leu2076Val (c.6226C>G) is classified Uncertain significance in ABCA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.0793); Very rare (popmax 0.00806%, afr).

How common is ABCA2 p.Leu2076Val (c.6226C>G) in the general population?

ABCA2 p.Leu2076Val (c.6226C>G) is very rare (popmax 0.00806%, afr) (gnomAD).

What do computational predictors say about ABCA2 p.Leu2076Val (c.6226C>G)?

AlphaMissense predicts likely benign (score 0.0793) — an in-silico prediction, not a clinical call.

ABCA2 p.Leu2076Val

c.6226C>G · VCV4260607

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0793 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00806%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0793	likely benign
REVEL	0.343	indeterminate
SaProt	LLR -8.25	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 5.5	GERP -0.99, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 3,800 bp · p 6.1e-23 · regional, not allelic
Overall
CADD	19.08	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 L2075V vs ClinVar L2076V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00806% African / African-American · 6/74,412 alleles

Filtering AF 0.00349% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0024%

Overall 0.0012% 19/1,588,578 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00806%	12,402
European (non-Finnish)	0.00111%	89,878

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.Leu2076Val
Coding: c.6226C>G
MANE Select: NM_001606
Type: single nucleotide variant
Location: chr9:137010320 (GRCh38)
Gene constraint: LOEUF 0.436 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 71.46
Residue 2076: 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-leu2076val (accessed [today's date]).

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