Is KL p.Pro643= (c.1929G>A) pathogenic?

KL p.Pro643= (c.1929G>A) is classified Likely benign in KL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-22). Very rare (popmax 0.00659%, sas).

How common is KL p.Pro643= (c.1929G>A) in the general population?

KL p.Pro643= (c.1929G>A) is very rare (popmax 0.00659%, sas) (gnomAD).

KL p.Pro643=

c.1929G>A · rs763527322 · VCV3007163

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.6	GERP -3.5
Overall
CADD	1.258	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/90,986 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00149% 24/1,612,778 alleles · very rare exomes 23/1,460,578 · genomes 1/152,200 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,164
Remaining individualsnot grpmax-eligible	0.0016%	62,400
European (non-Finnish)	0.00136%	73,696
African / African-American	0.00134%	74,902

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: KL
Protein: p.Pro643=
Coding: c.1929G>A
MANE Select: NM_004795
dbSNP: rs763527322
Type: single nucleotide variant
Location: chr13:33061008 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 6 PDB
Residue 643: the 'glycosyl hydrolase-1 2' region; a turn

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

Similar variants

KL c.1331-3C>A Uncertain significance ★★ same type
KL p.Ala3Thr Uncertain significance ★★ ⚠ same type
KL p.Ala50Val Uncertain significance ★★ ⚠ same type
KL p.Ala656Thr Uncertain significance ★★ ⚠ same type
KL p.Ala663Thr Uncertain significance ★★ ⚠ same type
KL p.Ala987Thr Uncertain significance ★★ ⚠ same type
KL p.Arg179Trp Uncertain significance ★★ ⚠ same type
KL p.Arg181Gln 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/kl-p-pro643 (accessed [today's date]).

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