Is CLPP p.His27Tyr (c.79C>T) pathogenic?

CLPP p.His27Tyr (c.79C>T) is classified Uncertain significance in CLPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-16). AlphaMissense: likely benign (0.0742); Very rare (popmax 0.000276%, nfe).

How common is CLPP p.His27Tyr (c.79C>T) in the general population?

CLPP p.His27Tyr (c.79C>T) is very rare (popmax 0.000276%, nfe) (gnomAD).

What do computational predictors say about CLPP p.His27Tyr (c.79C>T)?

AlphaMissense predicts likely benign (score 0.0742) — an in-silico prediction, not a clinical call.

CLPP p.His27Tyr

c.79C>T · VCV4282055

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0742 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000276%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0742	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -7.45	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 -0.08	GERP -2.9
Regional constraint	o/e 1.21	unconstrained · MANE · 328 bp · p 0.022 · regional, not allelic
Overall
CADD	10.71	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 0.000276% European (non-Finnish) · 3/1,088,500 alleles

Filtering AF 7.3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000236% 3/1,269,918 alleles · very rare

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: CLPP
Protein: p.His27Tyr
Coding: c.79C>T
MANE Select: NM_006012
Type: single nucleotide variant
Location: chr19:6361653 (GRCh38)
Gene constraint: LOEUF 0.936 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.68 · 32 PDB

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

Similar variants

CLPP c.368-2A>G Pathogenic/Likely pathogenic ★★ same type
CLPP p.Ala10Gly Uncertain significance ★★ ⚠ same type
CLPP p.Ala10Ser Uncertain significance ★★ ⚠ same type
CLPP p.Ala128Thr Uncertain significance ★★ ⚠ same type
CLPP p.Ala223Thr Uncertain significance ★★ ⚠ same type
CLPP p.Ala43Thr Uncertain significance ★★ ⚠ same type
CLPP p.Ala50Thr Uncertain significance ★★ ⚠ same type
CLPP p.Arg174Cys 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/clpp-p-his27tyr (accessed [today's date]).

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