Is PRKCSH p.Ser293Phe (c.878C>T) pathogenic?

PRKCSH p.Ser293Phe (c.878C>T) is classified Uncertain significance in PRKCSH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely benign (0.1026); Very rare (popmax 8.47e-05%, nfe).

How common is PRKCSH p.Ser293Phe (c.878C>T) in the general population?

PRKCSH p.Ser293Phe (c.878C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PRKCSH p.Ser293Phe (c.878C>T)?

AlphaMissense predicts likely benign (score 0.1026) — an in-silico prediction, not a clinical call.

PRKCSH p.Ser293Phe

c.878C>T · VCV3677357

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1026 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1026	likely benign
REVEL	0.161	moderately benign-leaning
SaProt	LLR -10.48	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.3, phastCons 0.029
Regional constraint	o/e 1.06	unconstrained · MANE · 12 kb · p 0.21 · regional, not allelic
Overall
CADD	18.62	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 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 0.000124% 2/1,614,080 alleles · very rare exomes 2/1,461,720 · genomes 0/152,360 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	63,918
European (non-Finnish)grpmax	8.47e-05%	1,180,030

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser293Phe
Coding: c.878C>T
MANE Select: NM_001289104
Type: single nucleotide variant
Location: chr19:11447467 (GRCh38)
Gene constraint: LOEUF 0.699 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 84.33 · 2 PDB
Residue 293: a UniProt-annotated variant site (in pcld1); the 'disordered' region

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

Similar variants

PRKCSH c.683+1G>A Likely pathogenic ★★ same type
PRKCSH c.684-1G>A Likely pathogenic ★★ same type
PRKCSH c.762+2T>C Likely pathogenic ★★ same type
PRKCSH p.Glu429Ter Pathogenic/Likely pathogenic ★★ same type
PRKCSH c.1286+4C>T Uncertain significance ★★ same type
PRKCSH p.Arg121Cys Uncertain significance ★★ ⚠ same type
PRKCSH p.Arg121His Uncertain significance ★★ ⚠ same type
PRKCSH p.Arg281Gln 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/prkcsh-p-ser293phe (accessed [today's date]).

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