Is ABCA12 p.Phe1111Leu (c.3333C>A) pathogenic?

ABCA12 p.Phe1111Leu (c.3333C>A) is classified Uncertain significance in ABCA12 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-27). AlphaMissense: likely pathogenic (0.9061); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with ABCA12 p.Phe1111Leu (c.3333C>A)?

ABCA12 p.Phe1111Leu (c.3333C>A) is associated with Inborn genetic diseases (ClinVar).

How common is ABCA12 p.Phe1111Leu (c.3333C>A) in the general population?

ABCA12 p.Phe1111Leu (c.3333C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ABCA12 p.Phe1111Leu (c.3333C>A)?

AlphaMissense predicts likely pathogenic (score 0.9061) — an in-silico prediction, not a clinical call.

ABCA12 p.Phe1111Leu

c.3333C>A · rs1471687214 · VCV2313958

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9061 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9061	likely pathogenic
REVEL	0.756	pathogenic-leaning
SaProt	LLR -7.04	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -4.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 85 kb · p 1.7e-09 · regional, not allelic
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,928 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,910 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,928
European (non-Finnish)	0.000339%	294,996

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.Phe1111Leu
Coding: c.3333C>A
MANE Select: NM_173076
dbSNP: rs1471687214
Type: single nucleotide variant
Location: chr2:214990993 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.32
Residue 1111: a UniProt-annotated variant site (in arci4b)

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

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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-phe1111leu (accessed [today's date]).

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