Is CPAP p.Pro1257Ala (c.3769C>G) pathogenic?

CPAP p.Pro1257Ala (c.3769C>G) is classified Uncertain significance in CPAP (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.0512); Very rare (popmax 0.00568%, nfe); Associated with microcephaly 6, primary, autosomal recessive.

What condition is associated with CPAP p.Pro1257Ala (c.3769C>G)?

CPAP p.Pro1257Ala (c.3769C>G) is associated with microcephaly 6, primary, autosomal recessive, Seckel syndrome 4 (ClinVar).

How common is CPAP p.Pro1257Ala (c.3769C>G) in the general population?

CPAP p.Pro1257Ala (c.3769C>G) is very rare (popmax 0.00568%, nfe) (gnomAD).

What do computational predictors say about CPAP p.Pro1257Ala (c.3769C>G)?

AlphaMissense predicts likely benign (score 0.0512) — an in-silico prediction, not a clinical call.

CPAP p.Pro1257Ala

c.3769C>G · rs201774037 · VCV882777

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0512 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00568%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly 6, primary, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.0512	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -10.57	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 30 kb · p 0.11 · regional, not allelic
Overall
CADD	8.051	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 0.00568% European (non-Finnish) · 67/1,179,900 alleles

Filtering AF 0.00454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00417%

Overall 0.00459% 74/1,613,940 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,414
European (non-Finnish)grpmax	0.00568%	17,610
African / African-American	0.00133%	74,930

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: CPAP
Protein: p.Pro1257Ala
Coding: c.3769C>G
MANE Select: NM_018451
dbSNP: rs201774037
Type: single nucleotide variant
Location: chr13:24884018 (GRCh38)
Structure: AlphaFold pLDDT 56.70 · 6 PDB
Residue 1257: the 'interaction with stil' region

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

Disease context

microcephaly 6, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Seckel syndrome 4

Similar variants

CPAP p.Pro1257Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CPAP p.Pro1257Ser Uncertain significance ★★ ⚠ same residue
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

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-pro1257ala (accessed [today's date]).

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