Is CPAMD8 p.Arg631Pro (c.1892G>C) pathogenic?

CPAMD8 p.Arg631Pro (c.1892G>C) is classified Uncertain significance in CPAMD8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-26). AlphaMissense: ambiguous (0.4457); Very rare (popmax 0.007%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CPAMD8 p.Arg631Pro (c.1892G>C)?

CPAMD8 p.Arg631Pro (c.1892G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CPAMD8 p.Arg631Pro (c.1892G>C) in the general population?

CPAMD8 p.Arg631Pro (c.1892G>C) is very rare (popmax 0.007%, nfe) (gnomAD).

What do computational predictors say about CPAMD8 p.Arg631Pro (c.1892G>C)?

AlphaMissense predicts ambiguous (score 0.4457) — an in-silico prediction, not a clinical call.

CPAMD8 p.Arg631Pro

c.1892G>C · rs759959118 · VCV2409728

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4457 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.007%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4457	ambiguous
REVEL	0.238	benign-leaning
SaProt	LLR -7.41	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.19	GERP -0.12, phastCons 0.003
Regional constraint	o/e 0.97	unconstrained · MANE · 83 kb · p 0.29 · regional, not allelic
Overall
CADD	19.18	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 0.007% European (non-Finnish) · 82/1,170,850 alleles

Filtering AF 0.00576% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00529%

Overall 0.00564% 90/1,596,782 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00975%	10,261
European (non-Finnish)grpmax	0.007%	14,279
Finnishnot grpmax-eligible	0.00313%	31,902

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: CPAMD8
Protein: p.Arg631Pro
Coding: c.1892G>C
MANE Select: NM_015692
dbSNP: rs759959118
Type: single nucleotide variant
Location: chr19:16976018 (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.Arg950Ser 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-arg631pro (accessed [today's date]).

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