Is DTHD1 p.Cys86Arg (c.256T>C) pathogenic?

DTHD1 p.Cys86Arg (c.256T>C) is classified Uncertain significance in DTHD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-20). Ultra-rare (popmax 0.0171%, mid); Associated with Leber congenital amaurosis.

What condition is associated with DTHD1 p.Cys86Arg (c.256T>C)?

DTHD1 p.Cys86Arg (c.256T>C) is associated with Leber congenital amaurosis, muscular dystrophy (ClinVar).

How common is DTHD1 p.Cys86Arg (c.256T>C) in the general population?

DTHD1 p.Cys86Arg (c.256T>C) is ultra-rare (popmax 0.0171%, mid) (gnomAD).

How is Leber congenital amaurosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

DTHD1 p.Cys86Arg

c.256T>C · rs886037840 · VCV242990

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, mid)

Conditions

Leber congenital amaurosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.09	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.1	GERP -4
Regional constraint	o/e 0.99	unconstrained · MANE · 62 kb · p 0.66 · regional, not allelic
Overall
CADD	12.26	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0171% Middle Eastern · 1/5,846 alleles

Filtering AF 0.000836% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000677%

Overall 0.00168% 23/1,373,018 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0171%	5,846
Remaining individualsnot grpmax-eligible	0.00681%	14,688
Admixed American	0.00206%	48,604
European (non-Finnish)	0.00141%	70,804
South Asian	0.00125%	79,998

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.Cys86Arg
Coding: c.256T>C
MANE Select: NM_001170700
dbSNP: rs886037840
Type: single nucleotide variant
Location: chr4:36282014 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.99

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

Disease context

Leber congenital amaurosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: muscular dystrophy

For Leber congenital amaurosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

DTHD1 p.Cys86Tyr 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-cys86arg (accessed [today's date]).

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