Is PROK2 p.Ala127= (c.381C>G) pathogenic?

PROK2 p.Ala127= (c.381C>G) is classified Likely benign in PROK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-03-06). Very rare (popmax 0.000424%, nfe); Associated with PROK2-related disorder.

What condition is associated with PROK2 p.Ala127= (c.381C>G)?

PROK2 p.Ala127= (c.381C>G) is associated with PROK2-related disorder (ClinVar).

How common is PROK2 p.Ala127= (c.381C>G) in the general population?

PROK2 p.Ala127= (c.381C>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

PROK2 p.Ala127=

c.381C>G · VCV3356530

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

PROK2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -1.6, phastCons 1
Overall
CADD	7.706	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,536 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,480 alleles · very rare exomes 3/1,461,352 · genomes 2/152,128 · joint denominator

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: PROK2
Protein: p.Ala127=
Coding: c.381C>G
MANE Select: NM_001126128
Type: single nucleotide variant
Location: chr3:71772733 (GRCh38)
Gene constraint: LOEUF 1.052 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 69.22

Full PROK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PROK2-related disorder

Similar variants

PROK2 p.Ala24Pro Conflicting classifications of pathogenicity ⚠ same condition
PROK2 p.Ala24Ser Uncertain significance ⚠ same condition
PROK2 p.Arg73His Uncertain significance ⚠ same condition
PROK2 p.Asn121Lys Uncertain significance ⚠ same condition
PROK2 p.Cys5Phe Uncertain significance ⚠ same condition
PROK2 p.Gly42Arg Uncertain significance ⚠ same condition
PROK2 p.His104Tyr Uncertain significance ⚠ same condition
PROK2 p.Met44Val Uncertain significance same condition

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/prok2-p-ala127 (accessed [today's date]).

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