Is DTHD1 p.Arg371Cys (c.1111C>T) pathogenic?

DTHD1 p.Arg371Cys (c.1111C>T) is classified Uncertain significance in DTHD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-04). AlphaMissense: likely benign (0.079); Very rare (popmax 0.00476%, sas).

How common is DTHD1 p.Arg371Cys (c.1111C>T) in the general population?

DTHD1 p.Arg371Cys (c.1111C>T) is very rare (popmax 0.00476%, sas) (gnomAD).

What do computational predictors say about DTHD1 p.Arg371Cys (c.1111C>T)?

AlphaMissense predicts likely benign (score 0.079) — an in-silico prediction, not a clinical call.

DTHD1 p.Arg371Cys

c.1111C>T · rs1395400652 · VCV1417889

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.079 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00476%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.079	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -4.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.19	GERP -0.81
Regional constraint	o/e 0.99	unconstrained · MANE · 62 kb · p 0.66 · regional, not allelic
Overall
CADD	16.87	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R246C vs ClinVar R371C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00476% South Asian · 4/84,068 alleles

Filtering AF 0.00161% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.00213% 33/1,550,990 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00476%	21,017
African / African-American	0.00411%	24,329
Remaining individualsnot grpmax-eligible	0.00333%	30,059
Admixed American	0.00196%	50,972
European (non-Finnish)	0.00192%	52,135
Finnishnot grpmax-eligible	0.00168%	59,386

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.Arg371Cys
Coding: c.1111C>T
MANE Select: NM_001170700
dbSNP: rs1395400652
Type: single nucleotide variant
Location: chr4:36290596 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.99
Residue 246 UniProt numbering: the zu5 1 domain

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

Similar variants

DTHD1 p.Arg371His Benign/Likely benign ★★ 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.Arg447Gln Uncertain significance ★★ ⚠ same type
DTHD1 p.Arg447Ter 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-arg371cys (accessed [today's date]).

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