Is PROK2 p.Ala24Ser (c.70G>T) pathogenic?

PROK2 p.Ala24Ser (c.70G>T) is classified Uncertain significance in PROK2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-30). AlphaMissense: likely benign (0.0935); No allele count reported in gnomAD v4.1 (AN 1,249,824); Associated with PROK2-related disorder.

What condition is associated with PROK2 p.Ala24Ser (c.70G>T)?

PROK2 p.Ala24Ser (c.70G>T) is associated with PROK2-related disorder (ClinVar).

How common is PROK2 p.Ala24Ser (c.70G>T) in the general population?

PROK2 p.Ala24Ser (c.70G>T) is no allele count reported in gnomAD v4.1 (AN 1,249,824) (gnomAD).

What do computational predictors say about PROK2 p.Ala24Ser (c.70G>T)?

AlphaMissense predicts likely benign (score 0.0935) — an in-silico prediction, not a clinical call.

PROK2 p.Ala24Ser

c.70G>T · VCV3347735

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0935 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,249,824)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PROK2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0935	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -6.65	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	GERP -3.4
Regional constraint	o/e 0.96	unconstrained · MANE · 12 kb · p 0.61 · regional, not allelic
Overall
CADD	0.36	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

No allele count reported in gnomAD v4.1 (AN 1,249,824). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PROK2
Protein: p.Ala24Ser
Coding: c.70G>T
MANE Select: NM_001126128
Type: single nucleotide variant
Location: chr3:71784983 (GRCh38)
Gene constraint: LOEUF 1.052 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 69.22
Residue 24: a UniProt-annotated variant site (in hh4; phenotype consistent with kallmann syndrome)

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 residue
PROK2 p.Ala24Val Likely benign ★ same residue
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-ala24ser (accessed [today's date]).

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