Is CCNP p.Pro247Leu (c.740C>T) pathogenic?

CCNP p.Pro247Leu (c.740C>T) is classified Uncertain significance in CCNP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-24). AlphaMissense: ambiguous (0.5321); Ultra-rare (popmax 0.0145%, nfe).

How common is CCNP p.Pro247Leu (c.740C>T) in the general population?

CCNP p.Pro247Leu (c.740C>T) is ultra-rare (popmax 0.0145%, nfe) (gnomAD).

What do computational predictors say about CCNP p.Pro247Leu (c.740C>T)?

AlphaMissense predicts ambiguous (score 0.5321) — an in-silico prediction, not a clinical call.

CCNP p.Pro247Leu

c.740C>T · rs763112058 · VCV3140003

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5321 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0145%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5321	ambiguous
REVEL	0.314	indeterminate
SaProt	LLR -10.65	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 0.67, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 3,586 bp · p 0.45 · regional, not allelic
Overall
CADD	25.8	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 0.0145% European (non-Finnish) · 166/1,144,164 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.0123% 191/1,546,582 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0217%	4,604
European (non-Finnish)grpmax	0.0145%	6,893
Finnishnot grpmax-eligible	0.0135%	7,404
Admixed American	0.00397%	25,215
South Asian	0.00239%	41,924

Remaining individuals 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: CCNP
Protein: p.Pro247Leu
Coding: c.740C>T
MANE Select: NM_024877
dbSNP: rs763112058
Type: single nucleotide variant
Location: chr19:40223236 (GRCh38)
Gene constraint: LOEUF 1.397 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.87

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

Similar variants

CCNP p.Ala173Ser Uncertain significance ★ ⚠ same type
CCNP p.Ala186Val Uncertain significance ★ ⚠ same type
CCNP p.Ala243Val Uncertain significance ★ ⚠ same type
CCNP p.Ala265Thr Uncertain significance ★ ⚠ same type
CCNP p.Ala37Ser Uncertain significance ★ ⚠ same type
CCNP p.Ala68Glu Uncertain significance ★ ⚠ same type
CCNP p.Ala81Ser Uncertain significance ★ ⚠ same type
CCNP p.Arg101His 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/ccnp-p-pro247leu (accessed [today's date]).

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