Is DTHD1 p.Arg447Ter (c.1339C>T) pathogenic?

DTHD1 p.Arg447Ter (c.1339C>T) is classified Uncertain significance in DTHD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-11). Very rare (popmax 0.00786%, amr).

How common is DTHD1 p.Arg447Ter (c.1339C>T) in the general population?

DTHD1 p.Arg447Ter (c.1339C>T) is very rare (popmax 0.00786%, amr) (gnomAD).

DTHD1 p.Arg447Ter

c.1339C>T · rs970203447 · VCV2159773

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00786%, 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	predicted	premature termination codon in exon 4 of 10
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.096	GERP 0.21
Overall
CADD	33.0	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 0.00786% Admixed American · 4/50,896 alleles

Filtering AF 0.00263% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00153%

Overall 0.00084% 13/1,548,066 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00786%	12,724
South Asian	0.00598%	16,730
Ashkenazi Jewishnot grpmax-eligible	0.00351%	28,522
East Asian	0.00245%	40,842
European (non-Finnish)	0.000175%	572,331

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: DTHD1
Protein: p.Arg447Ter
Coding: c.1339C>T
MANE Select: NM_001170700
dbSNP: rs970203447
Type: single nucleotide variant
Location: chr4:36293646 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.99
Residue 447: the zu5 2 domain

Full DTHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DTHD1 p.Arg447Gln Uncertain significance ★★ ⚠ same residue
DTHD1 c.1218+1G>A Uncertain significance ★★ same type
DTHD1 c.1219-2A>G Uncertain significance ★★ same type
DTHD1 p.Ala552Ser Uncertain significance ★★ ⚠ same type
DTHD1 p.Ala811Asp Uncertain significance ★★ ⚠ same type
DTHD1 p.Arg326Gln Uncertain significance ★★ ⚠ same type
DTHD1 p.Arg371Cys Uncertain significance ★★ ⚠ same type
DTHD1 p.Arg548Trp 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/dthd1-p-arg447ter (accessed [today's date]).

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