Is ALPG p.Pro228Arg (c.683C>G) pathogenic?

ALPG p.Pro228Arg (c.683C>G) is classified Benign in ALPG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.3267); Common (popmax 16.4%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ALPG p.Pro228Arg (c.683C>G)?

AlphaMissense predicts likely benign (score 0.3267) — an in-silico prediction, not a clinical call.

ALPG p.Pro228Arg

Q: How common is ALPG p.Pro228Arg (c.683C>G) in the general population?

ALPG p.Pro228Arg (c.683C>G) is common (popmax 16.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.683C>G · rs75920311 · VCV770697

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3267 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 16.4%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3267	likely benign
REVEL	0.543	indeterminate
SaProt	LLR -13.93	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.68, phastCons 0.98
Regional constraint	o/e 0.54	unconstrained · MANE · 265 bp · p 6.5e-05 · regional, not allelic
Overall
CADD	18.2	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 16.4% African / African-American · 11,930/72,544 alleles

Filtering AF 16.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 16.1%

Overall 6.74% 104,670/1,551,900 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	16.4%	6
East Asian	13.7%	7
Ashkenazi Jewishnot grpmax-eligible	10.4%	10
Middle Eastern	9.6%	10
Remaining individualsnot grpmax-eligible	7.7%	13
Finnishnot grpmax-eligible	7.04%	14
South Asian	6.65%	15
European (non-Finnish)	5.77%	17
Amishnot grpmax-eligible	5.62%	18
Admixed American	5.5%	18

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.Pro228Arg
Coding: c.683C>G
MANE Select: NM_031313
dbSNP: rs75920311
Type: single nucleotide variant
Location: chr2:232408301 (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.Pro94Ser Benign ★★ ⚠ same type
ALPG p.Ser150= Benign ★★ same type
ALPG p.Tyr95Phe 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-pro228arg (accessed [today's date]).

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