Is CLTC p.Pro405Ala (c.1213C>G) pathogenic?

CLTC p.Pro405Ala (c.1213C>G) is classified Uncertain significance in CLTC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-01). AlphaMissense: likely benign (0.0878); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with CLTC p.Pro405Ala (c.1213C>G)?

CLTC p.Pro405Ala (c.1213C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CLTC p.Pro405Ala (c.1213C>G) in the general population?

CLTC p.Pro405Ala (c.1213C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CLTC p.Pro405Ala (c.1213C>G)?

AlphaMissense predicts likely benign (score 0.0878) — an in-silico prediction, not a clinical call.

CLTC p.Pro405Ala

c.1213C>G · rs1409711775 · VCV3004670

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0878 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0878	likely benign
REVEL	0.4	indeterminate
SaProt	LLR -9.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 23 kb · p 5.1e-71 · regional, not allelic
Overall
CADD	26.1	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,613,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
South Asian	0.0011%	91,088
European (non-Finnish)	0.000424%	235,989

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: CLTC
Protein: p.Pro405Ala
Coding: c.1213C>G
MANE Select: NM_004859
dbSNP: rs1409711775
Type: single nucleotide variant
Location: chr17:59661488 (GRCh38)
Gene constraint: LOEUF 0.104 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.62 · 10 PDB
Residue 405: the 'globular terminal domain' region

Full CLTC 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

CLTC p.Ala1259Thr Uncertain significance ★★ ⚠ same condition
CLTC p.Ala198Thr Uncertain significance ★★ ⚠ same condition
CLTC p.Arg923His Uncertain significance ★★ ⚠ same condition
CLTC p.Arg949His Uncertain significance ★★ ⚠ same condition
CLTC p.Asn1078Ser Uncertain significance ★★ ⚠ same condition
CLTC p.Asn1145Ser Uncertain significance ★★ ⚠ same condition
CLTC p.Asn340Ser Uncertain significance ★★ ⚠ same condition
CLTC p.Asn376Ser 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/cltc-p-pro405ala (accessed [today's date]).

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