Is ABCA12 p.Ser325Phe (c.974C>T) pathogenic?

ABCA12 p.Ser325Phe (c.974C>T) is classified Benign/Likely benign in ABCA12 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0947); Rare (popmax 0.914%, eas); Associated with Congenital ichthyosis of skin.

What condition is associated with ABCA12 p.Ser325Phe (c.974C>T)?

ABCA12 p.Ser325Phe (c.974C>T) is associated with Congenital ichthyosis of skin (ClinVar).

How common is ABCA12 p.Ser325Phe (c.974C>T) in the general population?

ABCA12 p.Ser325Phe (c.974C>T) is rare (popmax 0.914%, eas) (gnomAD).

What do computational predictors say about ABCA12 p.Ser325Phe (c.974C>T)?

AlphaMissense predicts likely benign (score 0.0947) — an in-silico prediction, not a clinical call.

ABCA12 p.Ser325Phe

c.974C>T · rs138402017 · VCV719072

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0947 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.914%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Congenital ichthyosis of skin

Computational evidence

Protein change
AlphaMissense	0.0947	likely benign
REVEL	0.162	moderately benign-leaning
SaProt	LLR -7.19	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 7.5	GERP 2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 94 kb · p 0.48 · regional, not allelic
Overall
CADD	18.69	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 0.914% East Asian · 410/44,856 alleles

Filtering AF 0.841% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.812%

Overall 0.0373% 602/1,613,640 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.914%	109
Remaining individualsnot grpmax-eligible	0.237%	422
Admixed American	0.0283%	3,530
South Asian	0.0176%	5,692
African / African-American	0.00667%	15,003
European (non-Finnish)	0.000509%	196,604

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.Ser325Phe
Coding: c.974C>T
MANE Select: NM_173076
dbSNP: rs138402017
Type: single nucleotide variant
Location: chr2:215036964 (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-ser325phe (accessed [today's date]).

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