Is CPE p.Ala72Val (c.215C>T) pathogenic?

CPE p.Ala72Val (c.215C>T) is classified Likely benign in CPE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.1657); Rare (popmax 0.179%, nfe).

How common is CPE p.Ala72Val (c.215C>T) in the general population?

CPE p.Ala72Val (c.215C>T) is rare (popmax 0.179%, nfe) (gnomAD).

What do computational predictors say about CPE p.Ala72Val (c.215C>T)?

AlphaMissense predicts likely benign (score 0.1657) — an in-silico prediction, not a clinical call.

CPE p.Ala72Val

c.215C>T · rs148489430 · VCV1610581

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1657 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.179%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1657	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -9.54	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 4.5	GERP -1.6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 118 kb · p 0.00025 · regional, not allelic
Overall
CADD	23.0	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 0.179% European (non-Finnish) · 2,105/1,178,806 alleles

Filtering AF 0.172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.17%

Overall 0.153% 2,463/1,610,356 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.341%	294
European (non-Finnish)grpmax	0.179%	560
Ashkenazi Jewishnot grpmax-eligible	0.169%	591
Remaining individualsnot grpmax-eligible	0.136%	733
Middle Eastern	0.0167%	5,974
Admixed American	0.01%	9,981
South Asian	0.00221%	45,318
African / African-American	0.00133%	75,012

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: CPE
Protein: p.Ala72Val
Coding: c.215C>T
MANE Select: NM_001873
dbSNP: rs148489430
Type: single nucleotide variant
Location: chr4:165379436 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 90.83
Residue 72: the peptidase m14 domain

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

Similar variants

CPE p.Arg121Ter Pathogenic ★★ same type
CPE p.Arg262Trp Uncertain significance ★★ ⚠ same type
CPE p.Arg297Trp Uncertain significance ★★ ⚠ same type
CPE p.Asp251Gly Uncertain significance ★★ ⚠ same type
CPE p.Asp304Ala Uncertain significance ★★ ⚠ same type
CPE p.Trp21Cys Uncertain significance ★★ ⚠ same type
CPE c.307+13C>T Likely benign ★★ same type
CPE c.672+11C>T Likely benign ★★ 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/cpe-p-ala72val (accessed [today's date]).

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