Is ACP4 p.Pro249Leu (c.746C>T) pathogenic?

ACP4 p.Pro249Leu (c.746C>T) is classified Pathogenic in ACP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-22). AlphaMissense: likely benign (0.1457); Absent from gnomAD v4.1; Associated with amelogenesis imperfecta, type 1J.

What condition is associated with ACP4 p.Pro249Leu (c.746C>T)?

ACP4 p.Pro249Leu (c.746C>T) is associated with amelogenesis imperfecta, type 1J (ClinVar).

How common is ACP4 p.Pro249Leu (c.746C>T) in the general population?

ACP4 p.Pro249Leu (c.746C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACP4 p.Pro249Leu (c.746C>T)?

AlphaMissense predicts likely benign (score 0.1457) — an in-silico prediction, not a clinical call.

ACP4 p.Pro249Leu

c.746C>T · rs1085307111 · VCV375694

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1457 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amelogenesis imperfecta, type 1J

Computational evidence

Protein change
AlphaMissense	0.1457	likely benign ⚠ discordant with ClinVar
REVEL	0.227	benign-leaning
SaProt	LLR -8.97	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 7.2	GERP 0.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 4,740 bp · p 0.54 · regional, not allelic
Overall
CADD	23.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACP4
Protein: p.Pro249Leu
Coding: c.746C>T
MANE Select: NM_033068
dbSNP: rs1085307111
Type: single nucleotide variant
Location: chr19:50793784 (GRCh38)
Gene constraint: LOEUF 1.413 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.30
Residue 249: a disulfide bond

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

Disease context

amelogenesis imperfecta, type 1J — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACP4 p.Arg111Cys Pathogenic/Likely pathogenic ★★ same condition
ACP4 c.645+1G>A Likely pathogenic ★ same condition
ACP4 p.Leu85Pro Pathogenic ★ same condition
ACP4 p.Met282Thr Pathogenic ★ ⚠ same condition
ACP4 p.Val246Met Likely pathogenic ★ ⚠ same condition
ACP4 p.Ala400Asp Uncertain significance ★ ⚠ same condition
ACP4 p.Leu209Pro Uncertain significance ★ ⚠ same condition
ACP4 p.Ser238Leu Conflicting classifications of pathogenicity ★ ⚠ 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/acp4-p-pro249leu (accessed [today's date]).

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