Is ACP4 p.Arg88Ser (c.262C>A) pathogenic?

ACP4 p.Arg88Ser (c.262C>A) is classified Uncertain significance in ACP4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-02-03). AlphaMissense: likely pathogenic (0.6846); Ultra-rare (popmax 0.0122%, eas); Associated with amelogenesis imperfecta.

What condition is associated with ACP4 p.Arg88Ser (c.262C>A)?

ACP4 p.Arg88Ser (c.262C>A) is associated with amelogenesis imperfecta (ClinVar).

How common is ACP4 p.Arg88Ser (c.262C>A) in the general population?

ACP4 p.Arg88Ser (c.262C>A) is ultra-rare (popmax 0.0122%, eas) (gnomAD).

How is Amelogenesis imperfecta inherited?

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

What do computational predictors say about ACP4 p.Arg88Ser (c.262C>A)?

AlphaMissense predicts likely pathogenic (score 0.6846) — an in-silico prediction, not a clinical call.

ACP4 p.Arg88Ser

c.262C>A · rs1190557090 · VCV1027404

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6846 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

amelogenesis imperfecta

Computational evidence

Protein change
AlphaMissense	0.6846	likely pathogenic
REVEL	0.53	indeterminate
SaProt	LLR -13.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 4,740 bp · p 0.54 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0122% East Asian · 5/40,928 alleles

Filtering AF 0.00479% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.000323% 5/1,548,714 alleles · ultra-rare

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: ACP4
Protein: p.Arg88Ser
Coding: c.262C>A
MANE Select: NM_033068
dbSNP: rs1190557090
Type: single nucleotide variant
Location: chr19:50790819 (GRCh38)
Gene constraint: LOEUF 1.413 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.30

Full ACP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

amelogenesis imperfecta — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Amelogenesis imperfecta (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked dominant
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (United States)

Similar variants

ACP4 p.Arg88Cys Uncertain significance ★ ⚠ same residue
ACP4 p.Gln117Arg Uncertain significance ★ same condition
ACP4 p.Ser238Leu Conflicting classifications of pathogenicity ★ ⚠ same condition
ACP4 p.Pro140Leu Uncertain significance ⚠ same condition
ACP4 p.Arg111Cys Pathogenic/Likely pathogenic ★★ same type
ACP4 c.550-4C>T Benign ★★ same type
ACP4 c.550-9C>T Benign ★★ same type
ACP4 p.Gly328Ala Benign ★★ same type

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/acp4-p-arg88ser (accessed [today's date]).

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