Is ABCA12 p.Ser459Thr (c.1376G>C) pathogenic?

ABCA12 p.Ser459Thr (c.1376G>C) is classified Benign/Likely benign in ABCA12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0916); Ultra-rare (popmax 0.0333%, amr); Associated with autosomal recessive congenital ichthyosis 4B.

What condition is associated with ABCA12 p.Ser459Thr (c.1376G>C)?

ABCA12 p.Ser459Thr (c.1376G>C) is associated with autosomal recessive congenital ichthyosis 4B (ClinVar).

How common is ABCA12 p.Ser459Thr (c.1376G>C) in the general population?

ABCA12 p.Ser459Thr (c.1376G>C) is ultra-rare (popmax 0.0333%, amr) (gnomAD).

How is Harlequin ichthyosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCA12 p.Ser459Thr (c.1376G>C)?

AlphaMissense predicts likely benign (score 0.0916) — an in-silico prediction, not a clinical call.

ABCA12 p.Ser459Thr

c.1376G>C · rs113112835 · VCV930799

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0916 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive congenital ichthyosis 4B

Computational evidence

Protein change
AlphaMissense	0.0916	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -6.79	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 1.5	GERP 0.28, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 94 kb · p 0.48 · regional, not allelic
Overall
CADD	10.25	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 0.0333% Admixed American · 20/59,998 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0218%

Overall 0.0207% 334/1,614,046 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0333%	3,000
European (non-Finnish)	0.0252%	3,973
Remaining individualsnot grpmax-eligible	0.0224%	4,463
African / African-American	0.00267%	37,464
South Asian	0.0011%	91,086

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.Ser459Thr
Coding: c.1376G>C
MANE Select: NM_173076
dbSNP: rs113112835
Type: single nucleotide variant
Location: chr2:215019708 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.32
Residue 459: a UniProt-annotated variant site (in arci4b); a UniProt-annotated variant site (in)

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

Disease context

autosomal recessive congenital ichthyosis 4B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Harlequin ichthyosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

ABCA12 c.985+1G>A Likely pathogenic ★★ same condition
ABCA12 p.Arg1297Ter Pathogenic ★★ same condition
ABCA12 p.Arg1515Ter Pathogenic ★★ same condition
ABCA12 p.Arg1950Ter Pathogenic ★★ same condition
ABCA12 p.Arg1960Ter Likely pathogenic ★★ same condition
ABCA12 p.Arg2204Ter Pathogenic ★★ same condition
ABCA12 p.Arg2426Gln Likely pathogenic ★★ same condition
ABCA12 p.Arg2482Ter Pathogenic ★★ 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-ser459thr (accessed [today's date]).

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