Is ACP5 p.Phe75= (c.225C>T) pathogenic?

ACP5 p.Phe75= (c.225C>T) is classified Benign/Likely benign in ACP5 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 16.9%, mid) — too common for a highly-penetrant pathogenic allele; Associated with Spondyloenchondrodysplasia with immune dysregulation.

What condition is associated with ACP5 p.Phe75= (c.225C>T)?

ACP5 p.Phe75= (c.225C>T) is associated with Spondyloenchondrodysplasia with immune dysregulation (ClinVar).

ACP5 p.Phe75=

Q: How common is ACP5 p.Phe75= (c.225C>T) in the general population?

ACP5 p.Phe75= (c.225C>T) is common (popmax 16.9%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.225C>T · rs62638747 · VCV257477

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 16.9%, mid) — too common for a highly-penetrant pathogenic allele

Conditions

Spondyloenchondrodysplasia with immune dysregulation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.6	GERP 0.43, phastCons 1
Overall
CADD	9.839	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 16.9% Middle Eastern · 1,026/6,062 alleles

Filtering AF 16.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 15.7%

Overall 11.4% 183,734/1,613,984 alleles · common exomes 169,407/1,461,790 · genomes 14,327/152,194 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	16.9%	6
Amishnot grpmax-eligible	15.5%	6
Finnishnot grpmax-eligible	15.1%	7
Ashkenazi Jewishnot grpmax-eligible	12.4%	8
European (non-Finnish)	12.3%	8
Remaining individualsnot grpmax-eligible	11.2%	9
South Asian	9.64%	10
Admixed American	7.22%	14
African / African-American	3.82%	26
East Asian	2.45%	41

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: ACP5
Protein: p.Phe75=
Coding: c.225C>T
MANE Select: NM_001611
dbSNP: rs62638747
Type: single nucleotide variant
Location: chr19:11577093 (GRCh38)
Gene constraint: LOEUF 1.14 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 94.82 · 2 PDB
Residue 75: a turn

Full ACP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Spondyloenchondrodysplasia with immune dysregulation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACP5 p.Arg176Ter Pathogenic ★★ same condition
ACP5 p.Gln184Ter Pathogenic/Likely pathogenic ★★ same condition
ACP5 p.Gly109Arg Pathogenic/Likely pathogenic ★★ same condition
ACP5 p.Met264Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition
ACP5 p.Tyr123Ter Pathogenic ★★ same condition
ACP5 p.Tyr246Ter Pathogenic/Likely pathogenic ★★ same condition
ACP5 p.Tyr74Ter Pathogenic/Likely pathogenic ★★ same condition
ACP5 p.Ala19Val Uncertain significance ★★ ⚠ 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/acp5-p-phe75 (accessed [today's date]).

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