Is PRKCSH p.Leu289Phe (c.865C>T) pathogenic?

PRKCSH p.Leu289Phe (c.865C>T) is classified Uncertain significance in PRKCSH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-02). AlphaMissense: likely benign (0.0727); Very rare (popmax 0.00439%, sas); Associated with Inborn genetic diseases.

What condition is associated with PRKCSH p.Leu289Phe (c.865C>T)?

PRKCSH p.Leu289Phe (c.865C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PRKCSH p.Leu289Phe (c.865C>T) in the general population?

PRKCSH p.Leu289Phe (c.865C>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about PRKCSH p.Leu289Phe (c.865C>T)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

PRKCSH p.Leu289Phe

c.865C>T · rs747320872 · VCV1973183

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -8.82	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 -0.49	GERP -2.1
Regional constraint	o/e 1.06	unconstrained · MANE · 12 kb · p 0.21 · regional, not allelic
Overall
CADD	6.976	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 0.00439% South Asian · 4/91,068 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000342% 5/1,461,684 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,767
European (non-Finnish)	8.47e-05%	1,180,027

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: PRKCSH
Protein: p.Leu289Phe
Coding: c.865C>T
MANE Select: NM_001289104
dbSNP: rs747320872
Type: single nucleotide variant
Location: chr19:11447454 (GRCh38)
Gene constraint: LOEUF 0.699 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.33 · 2 PDB
Residue 289: the ef-hand 2 domain; a UniProt-annotated variant site (in pcld1); the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PRKCSH p.Leu289Arg Uncertain significance ★ ⚠ same residue
PRKCSH p.Arg381Cys Uncertain significance ★★ ⚠ same condition
PRKCSH p.Arg489His Uncertain significance ★★ ⚠ same condition
PRKCSH p.Asn412Ser Uncertain significance ★★ ⚠ same condition
PRKCSH p.Asp375Asn Uncertain significance ★★ ⚠ same condition
PRKCSH p.Asp41Glu Uncertain significance ★★ ⚠ same condition
PRKCSH p.Gln209His Uncertain significance ★★ ⚠ same condition
PRKCSH p.Glu132Lys Uncertain significance ★★ ⚠ same condition

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/prkcsh-p-leu289phe (accessed [today's date]).

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