Is CPAP p.Pro219Leu (c.656C>T) pathogenic?

CPAP p.Pro219Leu (c.656C>T) is classified Conflicting classifications of pathogenicity in CPAP (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1038); Rare (popmax 0.429%, afr); Associated with Seckel syndrome 4.

What condition is associated with CPAP p.Pro219Leu (c.656C>T)?

CPAP p.Pro219Leu (c.656C>T) is associated with Seckel syndrome 4, microcephaly 6, primary, autosomal recessive (ClinVar).

How common is CPAP p.Pro219Leu (c.656C>T) in the general population?

CPAP p.Pro219Leu (c.656C>T) is rare (popmax 0.429%, afr) (gnomAD).

What do computational predictors say about CPAP p.Pro219Leu (c.656C>T)?

AlphaMissense predicts likely benign (score 0.1038) — an in-silico prediction, not a clinical call.

CPAP p.Pro219Leu

c.656C>T · rs139844197 · VCV311629

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1038 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.429%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Seckel syndrome 4

Computational evidence

Protein change
AlphaMissense	0.1038	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -7.46	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 4.6	GERP 0.82, phastCons 0.92
Regional constraint	o/e 0.96	unconstrained · MANE · 30 kb · p 0.11 · regional, not allelic
Overall
CADD	14.44	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 0.429% African / African-American · 322/75,018 alleles

Filtering AF 0.391% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.376%

Overall 0.0245% 396/1,614,122 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.429%	233
Admixed American	0.06%	1,667
Remaining individualsnot grpmax-eligible	0.0304%	3,290
European (non-Finnish)	0.00161%	62,106

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: CPAP
Protein: p.Pro219Leu
Coding: c.656C>T
MANE Select: NM_018451
dbSNP: rs139844197
Type: single nucleotide variant
Location: chr13:24909999 (GRCh38)
Structure: AlphaFold pLDDT 56.70 · 6 PDB

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

Disease context

Seckel syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: microcephaly 6, primary, autosomal recessive

Similar variants

CPAP p.Arg1298Gln Likely pathogenic ★★ same condition
CPAP p.Arg378Ter Pathogenic ★★ same condition
CPAP p.Arg566Ter Pathogenic/Likely pathogenic ★★ same condition
CPAP p.Arg958Ter Pathogenic/Likely pathogenic ★★ same condition
CPAP p.Gln14Ter Pathogenic/Likely pathogenic ★★ same condition
CPAP p.Gln657Ter Pathogenic/Likely pathogenic ★★ same condition
CPAP p.Glu212Ter Pathogenic/Likely pathogenic ★★ same condition
CPAP p.Glu955Ter Pathogenic/Likely pathogenic ★★ same condition

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/cpap-p-pro219leu (accessed [today's date]).

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