Is CTDSPL2 p.Met425Val (c.1273A>G) pathogenic?

CTDSPL2 p.Met425Val (c.1273A>G) is classified Uncertain significance in CTDSPL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-23). AlphaMissense: likely benign (0.0681); Ultra-rare (popmax 0.0958%, afr).

How common is CTDSPL2 p.Met425Val (c.1273A>G) in the general population?

CTDSPL2 p.Met425Val (c.1273A>G) is ultra-rare (popmax 0.0958%, afr) (gnomAD).

What do computational predictors say about CTDSPL2 p.Met425Val (c.1273A>G)?

AlphaMissense predicts likely benign (score 0.0681) — an in-silico prediction, not a clinical call.

CTDSPL2 p.Met425Val

c.1273A>G · rs140533030 · VCV2519522

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0681 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0958%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0681	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -6.08	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 9,354 bp · p 1e-12 · regional, not allelic
Overall
CADD	18.23	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 0.0958% African / African-American · 71/74,150 alleles

Filtering AF 0.0778% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0712%

Overall 0.00493% 78/1,580,576 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0958%	1,044
Remaining individualsnot grpmax-eligible	0.00489%	20,451
Admixed American	0.00338%	29,572
European (non-Finnish)	0.000174%	576,362

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: CTDSPL2
Protein: p.Met425Val
Coding: c.1273A>G
MANE Select: NM_016396
dbSNP: rs140533030
Type: single nucleotide variant
Location: chr15:44521344 (GRCh38)
Gene constraint: LOEUF 0.184 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.94
Residue 425: the fcp1 homology domain

Full CTDSPL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CTDSPL2 p.Ala244Val Benign ★★ same type
CTDSPL2 p.Pro166= Benign ★★ same type
CTDSPL2 p.Ala199Pro Uncertain significance ★ ⚠ same type
CTDSPL2 p.Ala204Gly Uncertain significance ★ ⚠ same type
CTDSPL2 p.Ala231Thr Uncertain significance ★ ⚠ same type
CTDSPL2 p.Ala8Gly Uncertain significance ★ ⚠ same type
CTDSPL2 p.Ala8Thr Uncertain significance ★ ⚠ same type
CTDSPL2 p.Arg19Cys 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/ctdspl2-p-met425val (accessed [today's date]).

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