Is ALPP p.Ala209Ser (c.625G>T) pathogenic?

ALPP p.Ala209Ser (c.625G>T) is classified Uncertain significance in ALPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-16). AlphaMissense: likely benign (0.1017); Ultra-rare (popmax 0.0384%, nfe).

How common is ALPP p.Ala209Ser (c.625G>T) in the general population?

ALPP p.Ala209Ser (c.625G>T) is ultra-rare (popmax 0.0384%, nfe) (gnomAD).

What do computational predictors say about ALPP p.Ala209Ser (c.625G>T)?

AlphaMissense predicts likely benign (score 0.1017) — an in-silico prediction, not a clinical call.

ALPP p.Ala209Ser

c.625G>T · rs138033708 · VCV2365311

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1017 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0384%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1017	likely benign
REVEL	0.58	indeterminate
SaProt	LLR -9.44	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	phastCons 0.77
Regional constraint	o/e 0.97	unconstrained · MANE · 1,678 bp · p 0.53 · regional, not allelic
Overall
CADD	16.22	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 0.0384% European (non-Finnish) · 453/1,179,280 alleles

Filtering AF 0.0355% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0343%

Overall 0.0291% 469/1,612,098 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0384%	2,603
Remaining individualsnot grpmax-eligible	0.0128%	7,800
African / African-American	0.00667%	14,982
Finnishnot grpmax-eligible	0.00315%	31,783
Admixed American	0.00167%	59,934

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.Ala209Ser
Coding: c.625G>T
MANE Select: NM_001632
dbSNP: rs138033708
Type: single nucleotide variant
Location: chr2:232379904 (GRCh38)
Gene constraint: LOEUF 1.117 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.73 · 8 PDB
Residue 209: an α-helix

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

Similar variants

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
ALPP p.Phe331= 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-ala209ser (accessed [today's date]).

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