Is DTHD1 p.Val346Phe (c.1036G>T) pathogenic?

DTHD1 p.Val346Phe (c.1036G>T) is classified Uncertain significance in DTHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-25). AlphaMissense: likely pathogenic (0.7262); Very rare (popmax 8.72e-05%, nfe).

How common is DTHD1 p.Val346Phe (c.1036G>T) in the general population?

DTHD1 p.Val346Phe (c.1036G>T) is very rare (popmax 8.72e-05%, nfe) (gnomAD).

What do computational predictors say about DTHD1 p.Val346Phe (c.1036G>T)?

AlphaMissense predicts likely pathogenic (score 0.7262) — an in-silico prediction, not a clinical call.

DTHD1 p.Val346Phe

c.1036G>T · rs201684570 · VCV1486199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7262 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.72e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7262	likely pathogenic · top 8% in DTHD1
REVEL	0.206	benign-leaning
SaProt	LLR -11.96	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.71, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 62 kb · p 0.66 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V221F vs ClinVar V346F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.72e-05% European (non-Finnish) · 1/1,146,972 alleles

Overall 6.44e-05% 1/1,551,592 alleles · very rare exomes 1/1,399,352 · genomes 0/152,240 · joint denominator

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.Val346Phe
Coding: c.1036G>T
MANE Select: NM_001170700
dbSNP: rs201684570
Type: single nucleotide variant
Location: chr4:36290521 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.99
Residue 221 UniProt numbering: the zu5 1 domain

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

Similar variants

DTHD1 p.Val346Ile 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.Arg447Gln 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-val346phe (accessed [today's date]).

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