Is CLSTN3 p.Pro425Leu (c.1274C>T) pathogenic?

CLSTN3 p.Pro425Leu (c.1274C>T) is classified Uncertain significance in CLSTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-03). AlphaMissense: likely pathogenic (0.8511); Ultra-rare (popmax 0.0176%, sas).

How common is CLSTN3 p.Pro425Leu (c.1274C>T) in the general population?

CLSTN3 p.Pro425Leu (c.1274C>T) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

What do computational predictors say about CLSTN3 p.Pro425Leu (c.1274C>T)?

AlphaMissense predicts likely pathogenic (score 0.8511) — an in-silico prediction, not a clinical call.

CLSTN3 p.Pro425Leu

c.1274C>T · rs781625555 · VCV2293856

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8511 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8511	likely pathogenic
REVEL	0.263	benign-leaning
SaProt	LLR -6.81	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.73, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 27 kb · p 2.1e-07 · regional, not allelic
Overall
CADD	26.5	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 0.0176% South Asian · 16/91,064 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00888%

Overall 0.00911% 147/1,613,904 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,691
Middle Eastern	0.0165%	6,060
European (non-Finnish)	0.0105%	9,516
Remaining individualsnot grpmax-eligible	0.0048%	20,832
Admixed American	0.00333%	29,999
East Asian	0.00223%	44,866

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: CLSTN3
Protein: p.Pro425Leu
Coding: c.1274C>T
MANE Select: NM_014718
dbSNP: rs781625555
Type: single nucleotide variant
Location: chr12:7138018 (GRCh38)
Gene constraint: LOEUF 0.508 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 77.80

Full CLSTN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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CLSTN3 p.Ala152Val Uncertain significance ★ ⚠ same type
CLSTN3 p.Ala153Thr Uncertain significance ★ ⚠ same type
CLSTN3 p.Ala304Val Uncertain significance ★ ⚠ same type
CLSTN3 p.Ala312Pro Uncertain significance ★ ⚠ same type
CLSTN3 p.Ala312Val Uncertain significance ★ ⚠ same type
CLSTN3 p.Ala451Thr 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/clstn3-p-pro425leu (accessed [today's date]).

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