Is ABCA12 p.Arg986Trp (c.2956C>T) pathogenic?

ABCA12 p.Arg986Trp (c.2956C>T) is classified Pathogenic in ABCA12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-30). AlphaMissense: likely pathogenic (0.8659); Very rare (popmax 0.00333%, amr); Associated with lamellar ichthyosis.

What condition is associated with ABCA12 p.Arg986Trp (c.2956C>T)?

ABCA12 p.Arg986Trp (c.2956C>T) is associated with lamellar ichthyosis (ClinVar).

How common is ABCA12 p.Arg986Trp (c.2956C>T) in the general population?

ABCA12 p.Arg986Trp (c.2956C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

How is Lamellar ichthyosis inherited?

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

What do computational predictors say about ABCA12 p.Arg986Trp (c.2956C>T)?

AlphaMissense predicts likely pathogenic (score 0.8659) — an in-silico prediction, not a clinical call.

ABCA12 p.Arg986Trp

c.2956C>T · rs375702318 · VCV1455934

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8659 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lamellar ichthyosis

Computational evidence

Protein change
AlphaMissense	0.8659	likely pathogenic ✓ concordant with ClinVar
REVEL	0.901	moderately pathogenic-leaning
SaProt	LLR -10.74	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 85 kb · p 1.7e-09 · regional, not allelic
Overall
CADD	30.0	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 0.00333% Admixed American · 2/59,976 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.00124% 20/1,613,914 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0125%	8,001
Admixed Americangrpmax	0.00333%	29,988
East Asian	0.00223%	44,894
Remaining individualsnot grpmax-eligible	0.0016%	62,480
African / African-American	0.00134%	74,888
European (non-Finnish)	0.000593%	168,571

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg986Trp
Coding: c.2956C>T
MANE Select: NM_173076
dbSNP: rs375702318
Type: single nucleotide variant
Location: chr2:215000928 (GRCh38)
Gene constraint: LOEUF 0.582 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.32
Residue 986: a UniProt-annotated variant site (in arci4b)

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

Disease context

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

For Lamellar ichthyosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ABCA12 p.Arg986= Likely benign ★ same residue
ABCA12 c.2592+1G>A Likely pathogenic ★★ same condition
ABCA12 p.Arg1514Cys Pathogenic ★★ same condition
ABCA12 p.Arg1514His Pathogenic/Likely pathogenic ★★ same condition
ABCA12 p.Arg2204Ter Pathogenic ★★ same condition
ABCA12 p.Arg2426Gln Likely pathogenic ★★ same condition
ABCA12 p.Arg2482Ter Pathogenic ★★ same condition
ABCA12 p.Arg404Ter 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-arg986trp (accessed [today's date]).

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