Is CPLANE1 p.Thr421Ile (c.1262C>T) pathogenic?

CPLANE1 p.Thr421Ile (c.1262C>T) is classified Uncertain significance in CPLANE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-07). AlphaMissense: likely pathogenic (0.6979); Very rare (popmax 0.00119%, sas).

How common is CPLANE1 p.Thr421Ile (c.1262C>T) in the general population?

CPLANE1 p.Thr421Ile (c.1262C>T) is very rare (popmax 0.00119%, sas) (gnomAD).

What do computational predictors say about CPLANE1 p.Thr421Ile (c.1262C>T)?

AlphaMissense predicts likely pathogenic (score 0.6979) — an in-silico prediction, not a clinical call.

CPLANE1 p.Thr421Ile

c.1262C>T · rs752878745 · VCV2151250

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, sas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.6979	likely pathogenic · top 9% in CPLANE1
REVEL	0.253	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 139 kb · p 2.3e-06 · regional, not allelic
Overall
CADD	25.5	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 0.00119% South Asian · 1/84,052 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000258% 4/1,551,380 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00119%	84,052
European (non-Finnish)	0.000262%	382,297

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.Thr421Ile
Coding: c.1262C>T
MANE Select: NM_001384732
dbSNP: rs752878745
Type: single nucleotide variant
Location: chr5:37227677 (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

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-thr421ile (accessed [today's date]).

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