Is ABCA12 p.Ser408Pro (c.1222T>C) pathogenic?

ABCA12 p.Ser408Pro (c.1222T>C) is classified Benign/Likely benign in ABCA12 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.1769); Rare (popmax 0.816%, sas); Associated with Congenital ichthyosis of skin.

What condition is associated with ABCA12 p.Ser408Pro (c.1222T>C)?

ABCA12 p.Ser408Pro (c.1222T>C) is associated with Congenital ichthyosis of skin (ClinVar).

How common is ABCA12 p.Ser408Pro (c.1222T>C) in the general population?

ABCA12 p.Ser408Pro (c.1222T>C) is rare (popmax 0.816%, sas) (gnomAD).

What do computational predictors say about ABCA12 p.Ser408Pro (c.1222T>C)?

AlphaMissense predicts likely benign (score 0.1769) — an in-silico prediction, not a clinical call.

ABCA12 p.Ser408Pro

c.1222T>C · rs189141015 · VCV624177

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1769 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.816%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Congenital ichthyosis of skin

Computational evidence

Protein change
AlphaMissense	0.1769	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -7.42	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 1.1	GERP 2.3, phastCons 0.47
Regional constraint	o/e 1.03	unconstrained · MANE · 94 kb · p 0.48 · regional, not allelic
Overall
CADD	15.51	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 0.816% South Asian · 743/91,046 alleles

Filtering AF 0.767% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.748%

Overall 0.0678% 1,093/1,613,092 alleles · rare exomes 1,012/1,461,252 · genomes 81/151,840 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.816%	123
Middle Eastern	0.297%	336
Remaining individualsnot grpmax-eligible	0.0832%	1,201
Admixed American	0.0517%	1,934
European (non-Finnish)	0.0209%	4,795
African / African-American	0.00401%	24,953

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.Ser408Pro
Coding: c.1222T>C
MANE Select: NM_173076
dbSNP: rs189141015
Type: single nucleotide variant
Location: chr2:215025738 (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

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

Similar variants

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
ABCA12 c.*790A>G 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-ser408pro (accessed [today's date]).

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