Is KLK2 p.Ser23Pro (c.67T>C) pathogenic?

KLK2 p.Ser23Pro (c.67T>C) is classified Uncertain significance in KLK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.1185); Very rare (popmax 0.000254%, nfe).

How common is KLK2 p.Ser23Pro (c.67T>C) in the general population?

KLK2 p.Ser23Pro (c.67T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about KLK2 p.Ser23Pro (c.67T>C)?

AlphaMissense predicts likely benign (score 0.1185) — an in-silico prediction, not a clinical call.

KLK2 p.Ser23Pro

c.67T>C · VCV4544679

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1185 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1185	likely benign
REVEL	0.176	moderately benign-leaning
SaProt	LLR -6.22	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 -7.2
Regional constraint	o/e 1.01	unconstrained · MANE · 5,082 bp · p 0.82 · regional, not allelic
Overall
CADD	3.421	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 0.000254% European (non-Finnish) · 3/1,179,446 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,611,982 alleles · very rare exomes 2/1,459,896 · genomes 1/152,086 · 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: KLK2
Protein: p.Ser23Pro
Coding: c.67T>C
MANE Select: NM_005551
Type: single nucleotide variant
Location: chr19:50874741 (GRCh38)
Gene constraint: LOEUF 1.122 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.62 · 2 PDB

Full KLK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KLK2 p.Ala185Gly Uncertain significance ★ ⚠ same type
KLK2 p.Ala199Val Uncertain significance ★ ⚠ same type
KLK2 p.Ala258Val Uncertain significance ★ ⚠ same type
KLK2 p.Ala41Thr Uncertain significance ★ ⚠ same type
KLK2 p.Arg167His Uncertain significance ★ ⚠ same type
KLK2 p.Arg24Gln Uncertain significance ★ ⚠ same type
KLK2 p.Arg77Gln Uncertain significance ★ ⚠ same type
KLK2 p.Asn181Ser Uncertain significance ★ ⚠ 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/klk2-p-ser23pro (accessed [today's date]).

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