Is CPLANE1 p.Pro2804Ser (c.8410C>T) pathogenic?

CPLANE1 p.Pro2804Ser (c.8410C>T) is classified Conflicting classifications of pathogenicity in CPLANE1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-23). AlphaMissense: likely benign (0.1225); Ultra-rare (popmax 0.0773%, sas).

How common is CPLANE1 p.Pro2804Ser (c.8410C>T) in the general population?

CPLANE1 p.Pro2804Ser (c.8410C>T) is ultra-rare (popmax 0.0773%, sas) (gnomAD).

What do computational predictors say about CPLANE1 p.Pro2804Ser (c.8410C>T)?

AlphaMissense predicts likely benign (score 0.1225) — an in-silico prediction, not a clinical call.

CPLANE1 p.Pro2804Ser

c.8410C>T · rs377107065 · VCV1629876

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1225 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0773%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.1225	likely benign
REVEL	0.034	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 139 kb · p 2.3e-06 · regional, not allelic
Overall
CADD	19.65	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P2750S vs ClinVar P2804S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0773% South Asian · 70/90,504 alleles

Filtering AF 0.0628% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0574%

Overall 0.0113% 182/1,610,964 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0813%	1,229
South Asiangrpmax	0.0773%	1,293
Remaining individualsnot grpmax-eligible	0.0128%	7,794
European (non-Finnish)	0.0067%	14,917
African / African-American	0.00134%	74,816

Ashkenazi Jewish 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: CPLANE1
Protein: p.Pro2804Ser
Coding: c.8410C>T
MANE Select: NM_001384732
dbSNP: rs377107065
Type: single nucleotide variant
Location: chr5:37148232 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2804: a UniProt-annotated variant site (in ofd6; likely pathogenic)

Full CPLANE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPLANE1 c.1372-2A>G Pathogenic/Likely pathogenic ★★ same type
CPLANE1 c.2291+1G>A Likely pathogenic ★★ same type
CPLANE1 c.2291+2T>C Pathogenic/Likely pathogenic ★★ same type
CPLANE1 c.2292-1G>A Likely pathogenic ★★ same type
CPLANE1 c.2500+1G>A Likely pathogenic ★★ same type
CPLANE1 c.2920+1G>A Likely pathogenic ★★ same type
CPLANE1 c.3290-2A>G Pathogenic/Likely pathogenic ★★ same type
CPLANE1 c.3673-1G>C Pathogenic/Likely pathogenic ★★ 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/cplane1-p-pro2804ser (accessed [today's date]).

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