Is KLK8 p.Pro232Arg (c.695C>G) pathogenic?

KLK8 p.Pro232Arg (c.695C>G) is classified Uncertain significance in KLK8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: ambiguous (0.5464); Very rare (popmax 0.0011%, sas).

How common is KLK8 p.Pro232Arg (c.695C>G) in the general population?

KLK8 p.Pro232Arg (c.695C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about KLK8 p.Pro232Arg (c.695C>G)?

AlphaMissense predicts ambiguous (score 0.5464) — an in-silico prediction, not a clinical call.

KLK8 p.Pro232Arg

c.695C>G · VCV4544701

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5464 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Computational evidence

Protein change
AlphaMissense	0.5464	ambiguous
REVEL	0.604	indeterminate
SaProt	LLR -8.58	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 2, phastCons 1
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,088 alleles

Overall 0.000124% 2/1,614,212 alleles · very rare exomes 2/1,461,868 · genomes 0/152,344 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,088
European (non-Finnish)	8.47e-05%	1,180,025

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: KLK8
Protein: p.Pro232Arg
Coding: c.695C>G
MANE Select: NM_007196
Type: single nucleotide variant
Location: chr19:50996147 (GRCh38)
Gene constraint: LOEUF 0.973 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.79 · 2 PDB
Residue 232: the peptidase s1 domain; a β-strand

Full KLK8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KLK8 c.71-114T>C Uncertain significance ★ same type
KLK8 c.71-132G>A Uncertain significance ★ same type
KLK8 c.71-132G>T Uncertain significance ★ same type
KLK8 c.71-18C>G Uncertain significance ★ same type
KLK8 c.71-51C>T Uncertain significance ★ same type
KLK8 c.71-63G>C Uncertain significance ★ same type
KLK8 c.71-97G>A Uncertain significance ★ same type
KLK8 c.71-99C>T 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/klk8-p-pro232arg (accessed [today's date]).

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