Is CCDC87 p.Pro423Leu (c.1268C>T) pathogenic?

CCDC87 p.Pro423Leu (c.1268C>T) is classified Uncertain significance in CCDC87 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely benign (0.0863); Ultra-rare (popmax 0.0183%, amr).

How common is CCDC87 p.Pro423Leu (c.1268C>T) in the general population?

CCDC87 p.Pro423Leu (c.1268C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about CCDC87 p.Pro423Leu (c.1268C>T)?

AlphaMissense predicts likely benign (score 0.0863) — an in-silico prediction, not a clinical call.

CCDC87 p.Pro423Leu

c.1268C>T · VCV4649764

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0863 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0863	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -6.14	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 1.1	GERP 0.27, phastCons 0.15
Regional constraint	o/e 1.03	unconstrained · MANE · 2,546 bp · p 0.35 · regional, not allelic
Overall
CADD	19.28	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% Admixed American · 11/60,012 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00669% 108/1,613,676 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.19%	46
Admixed Americangrpmax	0.0183%	5,456
European (non-Finnish)	0.00619%	16,165
Remaining individualsnot grpmax-eligible	0.0048%	20,833
African / African-American	0.00133%	75,040

Amish 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: CCDC87
Protein: p.Pro423Leu
Coding: c.1268C>T
MANE Select: NM_018219
Type: single nucleotide variant
Location: chr11:66591748 (GRCh38)
Structure: AlphaFold pLDDT 62.53

Full CCDC87 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC87 p.Ala118Val Uncertain significance ★ ⚠ same type
CCDC87 p.Ala181Val Uncertain significance ★ ⚠ same type
CCDC87 p.Ala201Ser Uncertain significance ★ ⚠ same type
CCDC87 p.Ala201Val Uncertain significance ★ ⚠ same type
CCDC87 p.Ala322Glu Uncertain significance ★ ⚠ same type
CCDC87 p.Ala390Thr Uncertain significance ★ ⚠ same type
CCDC87 p.Ala530Val Uncertain significance ★ ⚠ same type
CCDC87 p.Ala626Thr Uncertain significance ★ ⚠ 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/ccdc87-p-pro423leu (accessed [today's date]).

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