Is CTDSPL2 p.Pro166= (c.498A>G) pathogenic?

CTDSPL2 p.Pro166= (c.498A>G) is classified Benign in CTDSPL2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-03-29). Common (popmax 5.59%, afr) — too common for a highly-penetrant pathogenic allele.

CTDSPL2 p.Pro166=

Q: How common is CTDSPL2 p.Pro166= (c.498A>G) in the general population?

CTDSPL2 p.Pro166= (c.498A>G) is common (popmax 5.59%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.498A>G · rs34612266 · VCV784321

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 5.59%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 1.5, phastCons 1
Overall
CADD	11.46	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.59% African / African-American · 4,194/74,990 alleles

Filtering AF 5.45% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.39%

Overall 0.306% 4,940/1,612,968 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.59%	18
Admixed American	0.422%	237
Remaining individualsnot grpmax-eligible	0.391%	256
Middle Eastern	0.231%	432
European (non-Finnish)	0.02%	5,000
South Asian	0.0011%	91,034

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.Pro166=
Coding: c.498A>G
MANE Select: NM_016396
dbSNP: rs34612266
Type: single nucleotide variant
Location: chr15:44490806 (GRCh38)
Gene constraint: LOEUF 0.184 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.94

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

Similar variants

CTDSPL2 p.Ala244Val 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
CTDSPL2 p.Arg224Cys 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-pro166 (accessed [today's date]).

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