Is ALPK2 p.Ala1306Pro (c.3916G>C) pathogenic?

ALPK2 p.Ala1306Pro (c.3916G>C) is classified Uncertain significance in ALPK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-13). AlphaMissense: likely benign (0.119); Very rare (popmax 0.00223%, eas).

How common is ALPK2 p.Ala1306Pro (c.3916G>C) in the general population?

ALPK2 p.Ala1306Pro (c.3916G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ALPK2 p.Ala1306Pro (c.3916G>C)?

AlphaMissense predicts likely benign (score 0.119) — an in-silico prediction, not a clinical call.

ALPK2 p.Ala1306Pro

c.3916G>C · rs2518875740 · VCV1736148

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.119 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.119	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -6.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -0.63
Regional constraint	o/e 0.91	unconstrained · MANE · 130 kb · p 6.4e-06 · regional, not allelic
Overall
CADD	18.43	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 0.00223% East Asian · 1/44,890 alleles

Overall 6.84e-05% 1/1,461,876 alleles · very rare

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: ALPK2
Protein: p.Ala1306Pro
Coding: c.3916G>C
MANE Select: NM_052947
dbSNP: rs2518875740
Type: single nucleotide variant
Location: chr18:58536271 (GRCh38)
Gene constraint: LOEUF 0.862 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 40.99
Residue 1306: the 'disordered' region

Full ALPK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALPK2 p.Ala1306= Likely benign ★ same residue
ALPK2 p.Thr2079Met Uncertain significance ★★ ⚠ same type
ALPK2 p.Arg1913Cys Benign/Likely benign ★★ same type
ALPK2 p.Asp390= Likely benign ★★ same type
ALPK2 p.Glu1525= Benign/Likely benign ★★ same type
ALPK2 p.Glu2056= Benign/Likely benign ★★ same type
ALPK2 p.Gly696= Likely benign ★★ same type
ALPK2 p.Ser163= Benign/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/alpk2-p-ala1306pro (accessed [today's date]).

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