Is KLK6 p.Pro173Ser (c.517C>T) pathogenic?

KLK6 p.Pro173Ser (c.517C>T) is classified Uncertain significance in KLK6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-08). AlphaMissense: likely benign (0.2145); Very rare (popmax 0.00653%, nfe).

How common is KLK6 p.Pro173Ser (c.517C>T) in the general population?

KLK6 p.Pro173Ser (c.517C>T) is very rare (popmax 0.00653%, nfe) (gnomAD).

What do computational predictors say about KLK6 p.Pro173Ser (c.517C>T)?

AlphaMissense predicts likely benign (score 0.2145) — an in-silico prediction, not a clinical call.

KLK6 p.Pro173Ser

c.517C>T · VCV4544693

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2145 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00653%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2145	likely benign
REVEL	0.618	indeterminate
SaProt	LLR -12.77	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Overall
CADD	22.6	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 0.00653% European (non-Finnish) · 77/1,179,956 alleles

Filtering AF 0.0053% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0049%

Overall 0.0049% 79/1,613,862 alleles · very rare exomes 77/1,461,780 · genomes 2/152,082 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00653%	15,324
Remaining individualsnot grpmax-eligible	0.0032%	31,238

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: KLK6
Protein: p.Pro173Ser
Coding: c.517C>T
MANE Select: NM_002774
Type: single nucleotide variant
Location: chr19:50961809 (GRCh38)
Structure: AlphaFold pLDDT 91.84 · 2 PDB
Residue 173: the peptidase s1 domain; a β-strand

Full KLK6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KLK1 p.His189= Benign/Likely benign ★★ same type
KLK6 p.Arg78Trp Benign ★★ ⚠ same type
KLK1 p.Ala244Ser Uncertain significance ★ ⚠ same type
KLK1 p.Ala244Val Uncertain significance ★ ⚠ same type
KLK1 p.Ala87Thr Uncertain significance ★ ⚠ same type
KLK1 p.Arg111Cys Uncertain significance ★ ⚠ same type
KLK1 p.Arg24Gln Uncertain significance ★ same type
KLK1 p.Arg57His 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/klk6-p-pro173ser (accessed [today's date]).

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