Is KL p.His552Pro (c.1655A>C) pathogenic?

KL p.His552Pro (c.1655A>C) is classified Uncertain significance in KL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: likely benign (0.1957); Rare (popmax 0.107%, eas).

How common is KL p.His552Pro (c.1655A>C) in the general population?

KL p.His552Pro (c.1655A>C) is rare (popmax 0.107%, eas) (gnomAD).

What do computational predictors say about KL p.His552Pro (c.1655A>C)?

AlphaMissense predicts likely benign (score 0.1957) — an in-silico prediction, not a clinical call.

KL p.His552Pro

c.1655A>C · VCV4761100

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1957 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.107%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1957	likely benign
REVEL	0.221	benign-leaning
SaProt	LLR -3.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.6	GERP 0.78, phastCons 0.95
Regional constraint	o/e 0.97	unconstrained · MANE · 48 kb · p 0.22 · regional, not allelic
Overall
CADD	21.5	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 0.107% East Asian · 48/44,884 alleles

Filtering AF 0.0829% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0743%

Overall 0.00366% 59/1,614,030 alleles · rare exomes 55/1,461,716 · genomes 4/152,314 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.107%	935
Remaining individualsnot grpmax-eligible	0.0032%	31,248
European (non-Finnish)	0.000763%	131,098

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.His552Pro
Coding: c.1655A>C
MANE Select: NM_004795
Type: single nucleotide variant
Location: chr13:33060734 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.48 · 6 PDB
Residue 552: the 'glycosyl hydrolase-1 2' region; a β-strand

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
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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-his552pro (accessed [today's date]).

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