Is ABCA12 p.Leu474Phe (c.1420C>T) pathogenic?

ABCA12 p.Leu474Phe (c.1420C>T) is classified Uncertain significance in ABCA12 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.1689); Ultra-rare (popmax 0.0165%, mid); Associated with Congenital ichthyosis of skin.

What condition is associated with ABCA12 p.Leu474Phe (c.1420C>T)?

ABCA12 p.Leu474Phe (c.1420C>T) is associated with Congenital ichthyosis of skin (ClinVar).

How common is ABCA12 p.Leu474Phe (c.1420C>T) in the general population?

ABCA12 p.Leu474Phe (c.1420C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ABCA12 p.Leu474Phe (c.1420C>T)?

AlphaMissense predicts likely benign (score 0.1689) — an in-silico prediction, not a clinical call.

ABCA12 p.Leu474Phe

c.1420C>T · rs886055611 · VCV334267

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1689 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Congenital ichthyosis of skin

Computational evidence

Protein change
AlphaMissense	0.1689	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -7.64	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 6.4	GERP 1.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 94 kb · p 0.48 · regional, not allelic
Overall
CADD	22.7	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,874 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
European (non-Finnish)	0.000169%	590,005

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.Leu474Phe
Coding: c.1420C>T
MANE Select: NM_173076
dbSNP: rs886055611
Type: single nucleotide variant
Location: chr2:215019664 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.32
Residue 474: a UniProt-annotated variant site (in arci4b)

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

Disease context

Congenital ichthyosis of skin — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCA12 p.Leu474= Likely benign ★ same residue
ABCA12 c.6962+5G>A Uncertain significance ★★ same condition
ABCA12 p.Ala1083Gly Uncertain significance ★★ ⚠ same condition
ABCA12 p.Gln2162Lys Uncertain significance ★★ ⚠ same condition
ABCA12 p.Glu2368Lys Uncertain significance ★★ ⚠ same condition
ABCA12 c.1062-8T>A Benign/Likely benign ★★ same condition
ABCA12 c.1287+14G>T Benign/Likely benign ★★ same condition
ABCA12 c.*26G>A Benign ★★ 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-leu474phe (accessed [today's date]).

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