Is CTH p.Asp5Glu (c.15C>A) pathogenic?

CTH p.Asp5Glu (c.15C>A) is classified Uncertain significance in CTH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-07-27). AlphaMissense: likely benign (0.0883); Rare (popmax 0.103%, amr); Associated with cystathioninuria.

What condition is associated with CTH p.Asp5Glu (c.15C>A)?

CTH p.Asp5Glu (c.15C>A) is associated with cystathioninuria (ClinVar).

How common is CTH p.Asp5Glu (c.15C>A) in the general population?

CTH p.Asp5Glu (c.15C>A) is rare (popmax 0.103%, amr) (gnomAD).

How is Cystathioninuria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CTH p.Asp5Glu (c.15C>A)?

AlphaMissense predicts likely benign (score 0.0883) — an in-silico prediction, not a clinical call.

CTH p.Asp5Glu

c.15C>A · rs143859234 · VCV876319

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0883 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.103%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cystathioninuria

Computational evidence

Protein change
AlphaMissense	0.0883	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -5.38	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 -0.26	GERP -3.6
Overall
CADD	4.405	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 0.103% Admixed American · 62/60,018 alleles

Filtering AF 0.0826% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0752%

Overall 0.0226% 364/1,614,018 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.439%	228
Admixed Americangrpmax	0.103%	968
Remaining individualsnot grpmax-eligible	0.0272%	3,677
European (non-Finnish)	0.0236%	4,229
African / African-American	0.00267%	37,520

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CTH
Protein: p.Asp5Glu
Coding: c.15C>A
MANE Select: NM_014312 · reported on NM_001902
dbSNP: rs143859234
Type: single nucleotide variant
Location: chr1:70411430 (GRCh38)
Structure: AlphaFold pLDDT 80.30

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

Disease context

cystathioninuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Cystathioninuria (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (Canada)

Similar variants

VSIG2 p.Pro5Leu Uncertain significance ★ ⚠ same residue
CTH c.647-15G>C Uncertain significance ★★ same condition
CTH p.Asp181Asn Uncertain significance ★★ ⚠ same condition
CTH p.Cys229Arg Uncertain significance ★★ ⚠ same condition
CTH p.Glu345Lys Uncertain significance ★★ ⚠ same condition
CTH p.Thr158Ile Uncertain significance ★★ ⚠ same condition
CTH c.-140A>T Likely benign ★★ same condition
CTH c.*523A>T Benign ★★ same condition

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/cth-p-asp5glu (accessed [today's date]).

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