Is CTDSPL p.Ser89Asn (c.266G>A) pathogenic?

CTDSPL p.Ser89Asn (c.266G>A) is classified Uncertain significance in CTDSPL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-28). AlphaMissense: likely benign (0.1721); Ultra-rare (popmax 0.0347%, amr).

How common is CTDSPL p.Ser89Asn (c.266G>A) in the general population?

CTDSPL p.Ser89Asn (c.266G>A) is ultra-rare (popmax 0.0347%, amr) (gnomAD).

What do computational predictors say about CTDSPL p.Ser89Asn (c.266G>A)?

AlphaMissense predicts likely benign (score 0.1721) — an in-silico prediction, not a clinical call.

CTDSPL p.Ser89Asn

c.266G>A · rs191830175 · VCV2594252

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1721 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1721	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -9.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.8	GERP 4.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 102 kb · p 0.55 · regional, not allelic
Overall
CADD	27.6	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 0.0347% Admixed American · 20/57,672 alleles

Filtering AF 0.023% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0192%

Overall 0.00221% 35/1,586,100 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0347%	2,884
Remaining individualsnot grpmax-eligible	0.0065%	15,384
South Asian	0.00229%	43,747
African / African-American	0.00136%	73,650
European (non-Finnish)	0.000689%	145,234

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: CTDSPL
Protein: p.Ser89Asn
Coding: c.266G>A
MANE Select: NM_001008392
dbSNP: rs191830175
Type: single nucleotide variant
Location: chr3:37957142 (GRCh38)
Gene constraint: LOEUF 0.369 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.64 · 1 PDB
Residue 89: an α-helix

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

Similar variants

CTDSPL p.Ala92Thr Uncertain significance ★ ⚠ same type
CTDSPL p.Arg184His Uncertain significance ★ ⚠ same type
CTDSPL p.Arg210Cys Uncertain significance ★ ⚠ same type
CTDSPL p.Arg262Gln Uncertain significance ★ ⚠ same type
CTDSPL p.Arg262Trp Uncertain significance ★ ⚠ same type
CTDSPL p.Asn12Ser Uncertain significance ★ ⚠ same type
CTDSPL p.Asn275Lys Uncertain significance ★ ⚠ same type
CTDSPL p.Asp265Asn 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/ctdspl-p-ser89asn (accessed [today's date]).

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