Is ACP5 p.Arg97His (c.290G>A) pathogenic?

ACP5 p.Arg97His (c.290G>A) is classified Uncertain significance in ACP5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-15). AlphaMissense: likely benign (0.0777); Very rare (popmax 0.00525%, nfe); Associated with Spondyloenchondrodysplasia with immune dysregulation.

What condition is associated with ACP5 p.Arg97His (c.290G>A)?

ACP5 p.Arg97His (c.290G>A) is associated with Spondyloenchondrodysplasia with immune dysregulation (ClinVar).

How common is ACP5 p.Arg97His (c.290G>A) in the general population?

ACP5 p.Arg97His (c.290G>A) is very rare (popmax 0.00525%, nfe) (gnomAD).

What do computational predictors say about ACP5 p.Arg97His (c.290G>A)?

AlphaMissense predicts likely benign (score 0.0777) — an in-silico prediction, not a clinical call.

ACP5 p.Arg97His

c.290G>A · rs777140546 · VCV573978

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0777 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00525%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spondyloenchondrodysplasia with immune dysregulation

Computational evidence

Protein change
AlphaMissense	0.0777	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -8.14	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 2.6	GERP 0.3, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 2,304 bp · p 0.00091 · regional, not allelic
Overall
CADD	21.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00525% European (non-Finnish) · 62/1,180,012 alleles

Filtering AF 0.00418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.0044% 71/1,613,930 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,497
European (non-Finnish)grpmax	0.00525%	19,032
East Asian	0.00446%	22,440
Admixed American	0.00334%	29,983

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg97His
Coding: c.290G>A
MANE Select: NM_001611
dbSNP: rs777140546
Type: single nucleotide variant
Location: chr19:11576815 (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 97: an α-helix

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.Arg97Cys Uncertain significance ★★ ⚠ same residue
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

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-arg97his (accessed [today's date]).

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