Is ABCA12 p.Asp99His (c.295G>C) pathogenic?

ABCA12 p.Asp99His (c.295G>C) is classified Uncertain significance in ABCA12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-21). AlphaMissense: likely benign (0.1004); Very rare (popmax 0.00669%, afr); Associated with Inborn genetic diseases.

What condition is associated with ABCA12 p.Asp99His (c.295G>C)?

ABCA12 p.Asp99His (c.295G>C) is associated with Inborn genetic diseases (ClinVar).

How common is ABCA12 p.Asp99His (c.295G>C) in the general population?

ABCA12 p.Asp99His (c.295G>C) is very rare (popmax 0.00669%, afr) (gnomAD).

What do computational predictors say about ABCA12 p.Asp99His (c.295G>C)?

AlphaMissense predicts likely benign (score 0.1004) — an in-silico prediction, not a clinical call.

ABCA12 p.Asp99His

c.295G>C · VCV3940132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1004 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1004	likely benign
REVEL	0.228	benign-leaning
SaProt	LLR -6.91	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 -0.93	GERP -5
Regional constraint	o/e 1.03	unconstrained · MANE · 94 kb · p 0.48 · regional, not allelic
Overall
CADD	6.314	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% African / African-American · 5/74,786 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00062% 10/1,612,720 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00669%	14,957
Admixed American	0.00668%	14,981
European (non-Finnish)	8.48e-05%	1,179,140

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: ABCA12
Protein: p.Asp99His
Coding: c.295G>C
MANE Select: NM_173076
Type: single nucleotide variant
Location: chr2:215064088 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.32

Full ABCA12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCA12 p.Ala134Ser Uncertain significance ★★ ⚠ same condition
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ABCA12 p.Ala833Val Uncertain significance ★★ ⚠ same condition
ABCA12 p.Arg1417Trp Uncertain significance ★★ ⚠ same condition
ABCA12 p.Arg1950Gln Uncertain significance ★★ ⚠ same condition
ABCA12 p.Asp505Val Uncertain significance ★★ ⚠ same condition
ABCA12 p.Asp756Val Uncertain significance ★★ ⚠ same condition
ABCA12 p.Gly2305Arg 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/abca12-p-asp99his (accessed [today's date]).

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