Is ALPG p.Pro445Ser (c.1333C>T) pathogenic?

ALPG p.Pro445Ser (c.1333C>T) is classified Uncertain significance in ALPG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-10). AlphaMissense: ambiguous (0.4662); Ultra-rare (popmax 0.0234%, amr).

How common is ALPG p.Pro445Ser (c.1333C>T) in the general population?

ALPG p.Pro445Ser (c.1333C>T) is ultra-rare (popmax 0.0234%, amr) (gnomAD).

What do computational predictors say about ALPG p.Pro445Ser (c.1333C>T)?

AlphaMissense predicts ambiguous (score 0.4662) — an in-silico prediction, not a clinical call.

ALPG p.Pro445Ser

c.1333C>T · VCV3528298

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4662 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0234%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4662	ambiguous
REVEL	0.701	pathogenic-leaning
SaProt	LLR -11.47	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 465 bp · p 0.026 · regional, not allelic
Overall
CADD	23.8	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 0.0234% Admixed American · 14/59,942 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00143% 23/1,612,688 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0234%	4,282
Remaining individualsnot grpmax-eligible	0.00961%	10,406
Finnishnot grpmax-eligible	0.00316%	31,620
European (non-Finnish)	8.48e-05%	1,179,778

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: ALPG
Protein: p.Pro445Ser
Coding: c.1333C>T
MANE Select: NM_031313
Type: single nucleotide variant
Location: chr2:232409606 (GRCh38)
Gene constraint: LOEUF 1.103 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.31

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

Similar variants

ALPG p.Arg498Pro Benign ★★ same type
ALPG p.Gly230= Benign ★★ same type
ALPG p.Gly500Asp Likely benign ★★ same type
ALPG p.His172= Benign/Likely benign ★★ same type
ALPG p.Leu8= Benign ★★ same type
ALPG p.Pro228Arg Benign ★★ ⚠ same type
ALPG p.Pro94Ser Benign ★★ ⚠ same type
ALPG p.Ser150= 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/alpg-p-pro445ser (accessed [today's date]).

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