Is ALPP p.Arg188Ser (c.562C>A) pathogenic?

ALPP p.Arg188Ser (c.562C>A) is classified Uncertain significance in ALPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-15). AlphaMissense: likely pathogenic (0.9517); Ultra-rare (popmax 0.0826%, afr).

How common is ALPP p.Arg188Ser (c.562C>A) in the general population?

ALPP p.Arg188Ser (c.562C>A) is ultra-rare (popmax 0.0826%, afr) (gnomAD).

What do computational predictors say about ALPP p.Arg188Ser (c.562C>A)?

AlphaMissense predicts likely pathogenic (score 0.9517) — an in-silico prediction, not a clinical call.

ALPP p.Arg188Ser

c.562C>A · rs142656870 · VCV2382193

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9517 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0826%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9517	likely pathogenic · top 5% in ALPP
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -15.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.041	phastCons 0.12
Regional constraint	o/e 0.97	unconstrained · MANE · 1,678 bp · p 0.53 · regional, not allelic
Overall
CADD	25.6	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 0.0826% African / African-American · 62/75,070 alleles

Filtering AF 0.066% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0601%

Overall 0.00397% 64/1,613,732 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0826%	1,211
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)	8.47e-05%	1,179,944

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: ALPP
Protein: p.Arg188Ser
Coding: c.562C>A
MANE Select: NM_001632
dbSNP: rs142656870
Type: single nucleotide variant
Location: chr2:232379841 (GRCh38)
Gene constraint: LOEUF 1.117 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.73 · 8 PDB
Residue 188: a disulfide bond

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

Similar variants

ALPP p.Arg188His Uncertain significance ★ ⚠ same residue
ALPP c.865+8C>T Likely benign ★★ same type
ALPP p.Ala176= Benign ★★ same type
ALPP p.Arg231Pro Benign ★★ same type
ALPP p.Arg36= Benign ★★ same type
ALPP p.Glu37Gln Benign ★★ same type
ALPP p.Gly233= Likely benign ★★ same type
ALPP p.Gly63= Likely 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/alpp-p-arg188ser (accessed [today's date]).

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