Is CTH p.Ser403Ile (c.1208G>T) pathogenic?

CTH p.Ser403Ile (c.1208G>T) is classified Benign in CTH (ClinVar, Multiple submitters, 5 submitters; last evaluated 2023-04-11). AlphaMissense: likely benign (0.0947); Common (popmax 40%, amr) — too common for a highly-penetrant pathogenic allele; Associated with cystathioninuria.

What condition is associated with CTH p.Ser403Ile (c.1208G>T)?

CTH p.Ser403Ile (c.1208G>T) is associated with cystathioninuria (ClinVar).

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.Ser403Ile (c.1208G>T)?

AlphaMissense predicts likely benign (score 0.0947) — an in-silico prediction, not a clinical call.

CTH p.Ser403Ile

Q: How common is CTH p.Ser403Ile (c.1208G>T) in the general population?

CTH p.Ser403Ile (c.1208G>T) is common (popmax 40%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1208G>T · rs1021737 · VCV2941

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0947 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 40%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cystathioninuria

Computational evidence

Protein change
AlphaMissense	0.0947	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -7.64	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 0.23	GERP -2.2
Overall
CADD	15.98	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 40% Admixed American · 24,008/59,966 alleles

Filtering AF 39.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 39.4%

Overall 28% 450,391/1,608,522 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	40%	2
Amishnot grpmax-eligible	31.9%	3
European (non-Finnish)	29.1%	3
Finnishnot grpmax-eligible	28.5%	4
Remaining individualsnot grpmax-eligible	27%	4
Ashkenazi Jewishnot grpmax-eligible	26.7%	4
South Asian	23.9%	4
East Asian	23.5%	4
Middle Eastern	21.1%	5
African / African-American	9.81%	10

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.Ser403Ile
Coding: c.1208G>T
MANE Select: NM_014312 · reported on NM_001902
dbSNP: rs1021737
Type: single nucleotide variant
Location: chr1:70439117 (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

CTH c.647-15G>C Uncertain significance ★★ same condition
CTH p.Asp181Asn Uncertain significance ★★ ⚠ same condition
CTH p.Asp5Glu 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-ser403ile (accessed [today's date]).

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