Is PROK2 p.Pro16Ser (c.46C>T) pathogenic?

PROK2 p.Pro16Ser (c.46C>T) is classified Uncertain significance in PROK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-25). AlphaMissense: likely benign (0.0877); Very rare (popmax 0.00313%, eas); Associated with Inborn genetic diseases.

What condition is associated with PROK2 p.Pro16Ser (c.46C>T)?

PROK2 p.Pro16Ser (c.46C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PROK2 p.Pro16Ser (c.46C>T) in the general population?

PROK2 p.Pro16Ser (c.46C>T) is very rare (popmax 0.00313%, eas) (gnomAD).

What do computational predictors say about PROK2 p.Pro16Ser (c.46C>T)?

AlphaMissense predicts likely benign (score 0.0877) — an in-silico prediction, not a clinical call.

PROK2 p.Pro16Ser

c.46C>T · rs1369054897 · VCV3219007

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0877 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00313%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0877	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -7.43	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 1.6	GERP -0.13, phastCons 0.084
Regional constraint	o/e 0.96	unconstrained · MANE · 12 kb · p 0.61 · regional, not allelic
Overall
CADD	17.14	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 0.00313% East Asian · 1/31,960 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.2e-05%

Overall 0.00032% 4/1,248,326 alleles · very rare exomes 3/1,096,184 · genomes 1/152,142 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00313%	31,960
European (non-Finnish)	0.000302%	331,219

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.Pro16Ser
Coding: c.46C>T
MANE Select: NM_001126128
dbSNP: rs1369054897
Type: single nucleotide variant
Location: chr3:71785007 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PROK2 p.Arg122Gln Uncertain significance ★★ ⚠ same condition
PROK2 p.Asp66Asn Uncertain significance ★★ ⚠ same condition
PROK2 p.Val29Met Uncertain significance ★★ ⚠ same condition
PROK2 p.Ala33Pro Uncertain significance ★ ⚠ same condition
PROK2 p.Arg117Gln Uncertain significance ★ ⚠ same condition
PROK2 p.Asn76Ser Uncertain significance ★ ⚠ same condition
PROK2 p.His69Tyr Uncertain significance ★ ⚠ same condition
PROK2 p.Leu15Gln 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-pro16ser (accessed [today's date]).

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