Is ALPP p.Arg272Ser (c.814C>A) pathogenic?

ALPP p.Arg272Ser (c.814C>A) is classified Uncertain significance in ALPP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-05). AlphaMissense: ambiguous (0.5538); Very rare (popmax 0.00801%, afr).

How common is ALPP p.Arg272Ser (c.814C>A) in the general population?

ALPP p.Arg272Ser (c.814C>A) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about ALPP p.Arg272Ser (c.814C>A)?

AlphaMissense predicts ambiguous (score 0.5538) — an in-silico prediction, not a clinical call.

ALPP p.Arg272Ser

c.814C>A · VCV3533900

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5538 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Computational evidence

Protein change
AlphaMissense	0.5538	ambiguous
REVEL	0.621	indeterminate
SaProt	LLR -12.47	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.94	phastCons 0.21
Regional constraint	o/e 0.97	unconstrained · MANE · 1,678 bp · p 0.53 · regional, not allelic
Overall
CADD	22.9	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

Grpmax group 0.00801% African / African-American · 6/74,888 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00235% 38/1,613,824 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,481
European (non-Finnish)	0.00263%	38,064
Admixed American	0.00167%	59,992

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.Arg272Ser
Coding: c.814C>A
MANE Select: NM_001632
Type: single nucleotide variant
Location: chr2:232380441 (GRCh38)
Gene constraint: LOEUF 1.117 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.73 · 8 PDB
Residue 272: an α-helix

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

Similar variants

ALPP p.Arg272Cys Uncertain significance ★ ⚠ same residue
ALPP p.Arg272Gly 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

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-arg272ser (accessed [today's date]).

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