Is CPAMD8 p.Pro227Ser (c.679C>T) pathogenic?

CPAMD8 p.Pro227Ser (c.679C>T) is classified Uncertain significance in CPAMD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely pathogenic (0.6712); Very rare (popmax 0.00477%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CPAMD8 p.Pro227Ser (c.679C>T)?

CPAMD8 p.Pro227Ser (c.679C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CPAMD8 p.Pro227Ser (c.679C>T) in the general population?

CPAMD8 p.Pro227Ser (c.679C>T) is very rare (popmax 0.00477%, nfe) (gnomAD).

What do computational predictors say about CPAMD8 p.Pro227Ser (c.679C>T)?

AlphaMissense predicts likely pathogenic (score 0.6712) — an in-silico prediction, not a clinical call.

CPAMD8 p.Pro227Ser

c.679C>T · VCV4233187

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6712 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00477%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6712	likely pathogenic
REVEL	0.32	indeterminate
SaProt	LLR -9.67	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 0.0018 · regional, not allelic
Overall
CADD	23.6	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 0.00477% European (non-Finnish) · 56/1,173,934 alleles

Filtering AF 0.00377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00339%

Overall 0.0038% 61/1,603,816 alleles · very rare exomes 54/1,451,936 · genomes 7/151,880 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00477%	20,963
African / African-American	0.00402%	24,871
Remaining individualsnot grpmax-eligible	0.00322%	31,009

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: CPAMD8
Protein: p.Pro227Ser
Coding: c.679C>T
MANE Select: NM_015692
Type: single nucleotide variant
Location: chr19:17002345 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.99

Full CPAMD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CPAMD8 c.-54C>G Uncertain significance ★★ same condition
CPAMD8 p.Ala1236Thr Uncertain significance ★★ ⚠ same condition
CPAMD8 p.Ala1468Glu Uncertain significance ★★ ⚠ same condition
CPAMD8 p.Ala490Thr Uncertain significance ★★ ⚠ same condition
CPAMD8 p.Arg1186His Uncertain significance ★★ ⚠ same condition
CPAMD8 p.Arg171Gln Uncertain significance ★★ ⚠ same condition
CPAMD8 p.Arg402His Uncertain significance ★★ ⚠ same condition
CPAMD8 p.Arg631Pro Uncertain significance ★★ ⚠ 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/cpamd8-p-pro227ser (accessed [today's date]).

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