Is PRKCH p.Val641Phe (c.1921G>T) pathogenic?

PRKCH p.Val641Phe (c.1921G>T) is classified Uncertain significance in PRKCH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). AlphaMissense: likely pathogenic (0.5807); Very rare (popmax 0.00246%, nfe).

How common is PRKCH p.Val641Phe (c.1921G>T) in the general population?

PRKCH p.Val641Phe (c.1921G>T) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about PRKCH p.Val641Phe (c.1921G>T)?

AlphaMissense predicts likely pathogenic (score 0.5807) — an in-silico prediction, not a clinical call.

PRKCH p.Val641Phe

c.1921G>T · VCV3938147

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5807 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5807	likely pathogenic
REVEL	0.407	indeterminate
SaProt	LLR -9.24	tolerated
⇒ AlphaMissense calls this damaging; SaProt 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
Regional constraint	o/e 1.12	unconstrained · MANE · 1,995 bp · p 0.28 · regional, not allelic
Overall
CADD	29.6	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 0.00246% European (non-Finnish) · 29/1,179,490 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00186% 30/1,611,286 alleles · very rare exomes 29/1,459,460 · genomes 1/151,826 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00246%	40,672
Remaining individualsnot grpmax-eligible	0.0016%	62,426

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: PRKCH
Protein: p.Val641Phe
Coding: c.1921G>T
MANE Select: NM_006255
Type: single nucleotide variant
Location: chr14:61549700 (GRCh38)
Gene constraint: LOEUF 0.467 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.75 · 4 PDB
Residue 641: the agc-kinase c-terminal domain

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

Similar variants

PRKCH p.Ile445= Benign ★★ same type
PRKCH c.578+3A>G Uncertain significance ★ same type
PRKCH p.Ala114Val Uncertain significance ★ ⚠ same type
PRKCH p.Ala539Thr Uncertain significance ★ ⚠ same type
PRKCH p.Ala620Val Uncertain significance ★ ⚠ same type
PRKCH p.Arg110Cys Uncertain significance ★ ⚠ same type
PRKCH p.Arg149Trp Uncertain significance ★ ⚠ same type
PRKCH p.Arg26His 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/prkch-p-val641phe (accessed [today's date]).

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