Is THBD p.Cys466Ter (c.1398C>A) pathogenic?

THBD p.Cys466Ter (c.1398C>A) is classified Uncertain significance in THBD (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-30). Very rare (popmax 0.00167%, amr).

How common is THBD p.Cys466Ter (c.1398C>A) in the general population?

THBD p.Cys466Ter (c.1398C>A) is very rare (popmax 0.00167%, amr) (gnomAD).

THBD p.Cys466Ter

c.1398C>A · VCV4944579

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (1 of 1) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -2.8
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,000 alleles

Overall 0.000124% 2/1,613,178 alleles · very rare exomes 1/1,460,932 · genomes 1/152,246 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,000
Finnishnot grpmax-eligible	0.00158%	63,248

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: THBD
Protein: p.Cys466Ter
Coding: c.1398C>A
MANE Select: NM_000361
Type: single nucleotide variant
Location: chr20:23048107 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 466: the egf-like 6; calcium-binding domain; a disulfide bond; a β-strand

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

Similar variants

THBD p.Cys466Tyr Uncertain significance ★ ⚠ same residue
THBD p.Cys537Ter Pathogenic/Likely pathogenic ★★ same type
THBD p.Ala139Ser Uncertain significance ★★ ⚠ same type
THBD p.Ala21Ser Uncertain significance ★★ ⚠ same type
THBD p.Ala255Pro Uncertain significance ★★ ⚠ same type
THBD p.Ala271Thr Uncertain significance ★★ ⚠ same type
THBD p.Ala272Val Uncertain significance ★★ ⚠ same type
THBD p.Ala284Gly 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/thbd-p-cys466ter (accessed [today's date]).

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