Is CPLANE1 p.Leu725Ser (c.2174T>C) pathogenic?

CPLANE1 p.Leu725Ser (c.2174T>C) is classified Uncertain significance in CPLANE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-08). AlphaMissense: likely benign (0.2851); Ultra-rare (popmax 0.0167%, mid); Associated with Inborn genetic diseases.

What condition is associated with CPLANE1 p.Leu725Ser (c.2174T>C)?

CPLANE1 p.Leu725Ser (c.2174T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CPLANE1 p.Leu725Ser (c.2174T>C) in the general population?

CPLANE1 p.Leu725Ser (c.2174T>C) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about CPLANE1 p.Leu725Ser (c.2174T>C)?

AlphaMissense predicts likely benign (score 0.2851) — an in-silico prediction, not a clinical call.

CPLANE1 p.Leu725Ser

c.2174T>C · rs1175193491 · VCV1981597

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2851 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2851	likely benign
REVEL	0.257	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1.4, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 139 kb · p 2.3e-06 · regional, not allelic
Overall
CADD	22.0	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Middle Eastern · 1/5,986 alleles

Overall 0.000129% 2/1,551,270 alleles · ultra-rare exomes 2/1,398,914 · genomes 0/152,356 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,986
African / African-American	0.00137%	73,162

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.Leu725Ser
Coding: c.2174T>C
MANE Select: NM_001384732
dbSNP: rs1175193491
Type: single nucleotide variant
Location: chr5:37226421 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

Full CPLANE1 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

CPLANE1 c.3921+6T>G Uncertain significance ★★ same condition
CPLANE1 p.Ala77Ser Uncertain significance ★★ ⚠ same condition
CPLANE1 p.Arg1199Gln Uncertain significance ★★ ⚠ same condition
CPLANE1 p.Arg3015Cys Uncertain significance ★★ ⚠ same condition
CPLANE1 p.Asp2526Asn Uncertain significance ★★ ⚠ same condition
CPLANE1 p.Cys1280Tyr Uncertain significance ★★ ⚠ same condition
CPLANE1 p.Cys3057Gly Uncertain significance ★★ ⚠ same condition
CPLANE1 p.Cys525Arg 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/cplane1-p-leu725ser (accessed [today's date]).

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