Is CTU2 p.Ser158Leu (c.473C>T) pathogenic?

CTU2 p.Ser158Leu (c.473C>T) is classified Uncertain significance in CTU2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-26). AlphaMissense: likely benign (0.1412); Ultra-rare (popmax 0.0143%, sas).

How common is CTU2 p.Ser158Leu (c.473C>T) in the general population?

CTU2 p.Ser158Leu (c.473C>T) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about CTU2 p.Ser158Leu (c.473C>T)?

AlphaMissense predicts likely benign (score 0.1412) — an in-silico prediction, not a clinical call.

CTU2 p.Ser158Leu

c.473C>T · VCV3498550

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1412 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1412	likely benign
REVEL	0.341	indeterminate
SaProt	LLR -8.28	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 4.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.61	unconstrained · MANE · 8,717 bp · p 1.9e-57 · regional, not allelic
Overall
CADD	24.1	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 0.0143% South Asian · 13/90,920 alleles

Filtering AF 0.00846% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00662%

Overall 0.00248% 40/1,610,158 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	6,994
Remaining individualsnot grpmax-eligible	0.00482%	20,754
African / African-American	0.00401%	24,945
Admixed American	0.00334%	29,956
European (non-Finnish)	0.00161%	62,077

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: CTU2
Protein: p.Ser158Leu
Coding: c.473C>T
MANE Select: NM_001012759
Type: single nucleotide variant
Location: chr16:88712641 (GRCh38)
Gene constraint: LOEUF 1.535 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.27

Full CTU2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CTU2 p.Ser158= Likely benign ★★ same residue
CTU2 c.1420-1G>A Likely pathogenic ★★ same type
CTU2 c.282+5G>A Pathogenic ★★ same type
CTU2 p.Gln243Ter Pathogenic/Likely pathogenic ★★ same type
CTU2 p.Thr291= Pathogenic ★★ same type
CTU2 p.Ala176Val Uncertain significance ★★ ⚠ same type
CTU2 p.Ala400Thr Uncertain significance ★★ ⚠ same type
CTU2 p.Arg270Cys 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/ctu2-p-ser158leu (accessed [today's date]).

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