Is CNPPD1 p.Val252Ile (c.754G>A) pathogenic?

CNPPD1 p.Val252Ile (c.754G>A) is classified Uncertain significance in CNPPD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-04). AlphaMissense: likely benign (0.0981); Very rare (popmax 0.00401%, afr).

How common is CNPPD1 p.Val252Ile (c.754G>A) in the general population?

CNPPD1 p.Val252Ile (c.754G>A) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about CNPPD1 p.Val252Ile (c.754G>A)?

AlphaMissense predicts likely benign (score 0.0981) — an in-silico prediction, not a clinical call.

CNPPD1 p.Val252Ile

c.754G>A · VCV4230978

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0981	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -7.31	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 0.41	GERP -0.65, phastCons 0.029
Regional constraint	o/e 0.99	unconstrained · MANE · 4,239 bp · p 0.74 · regional, not allelic
Overall
CADD	17.62	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 0.00401% African / African-American · 3/74,858 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000606%

Overall 0.00118% 19/1,609,596 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,953
European (non-Finnish)	0.00127%	78,623
South Asian	0.0011%	90,992

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: CNPPD1
Protein: p.Val252Ile
Coding: c.754G>A
MANE Select: NM_015680
Type: single nucleotide variant
Location: chr2:219173065 (GRCh38)
Gene constraint: LOEUF 1.039 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.88

Full CNPPD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CNPPD1 p.Ala150Val Uncertain significance ★ ⚠ same type
CNPPD1 p.Ala155Thr Uncertain significance ★ ⚠ same type
CNPPD1 p.Ala161Val Uncertain significance ★ ⚠ same type
CNPPD1 p.Ala236Val Uncertain significance ★ ⚠ same type
CNPPD1 p.Ala246Val Uncertain significance ★ ⚠ same type
CNPPD1 p.Ala248Thr Uncertain significance ★ ⚠ same type
CNPPD1 p.Ala293Thr Uncertain significance ★ ⚠ same type
CNPPD1 p.Ala351Thr 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/cnppd1-p-val252ile (accessed [today's date]).

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