Is DNHD1 p.Leu1643= (c.4927C>T) pathogenic?

DNHD1 p.Leu1643= (c.4927C>T) is classified Benign in DNHD1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-02-07). Common (popmax 6.34%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with DNHD1-related disorder.

What condition is associated with DNHD1 p.Leu1643= (c.4927C>T)?

DNHD1 p.Leu1643= (c.4927C>T) is associated with DNHD1-related disorder (ClinVar).

DNHD1 p.Leu1643=

Q: How common is DNHD1 p.Leu1643= (c.4927C>T) in the general population?

DNHD1 p.Leu1643= (c.4927C>T) is common (popmax 6.34%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4927C>T · rs61735751 · VCV3056402

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 6.34%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

DNHD1-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.73, phastCons 1
Overall
CADD	5.956	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.34% European (non-Finnish) · 72,704/1,146,976 alleles

Filtering AF 6.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.28%

Overall 5.3% 82,290/1,551,792 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	13.7%	7
European (non-Finnish)grpmax	6.34%	16
Finnishnot grpmax-eligible	5.4%	19
Remaining individualsnot grpmax-eligible	4.07%	25
Ashkenazi Jewishnot grpmax-eligible	3.34%	30
Admixed American	1.6%	62
South Asian	1.52%	66
African / African-American	0.916%	109
Middle Eastern	0.818%	122
East Asian	0.00977%	10,231

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DNHD1
Protein: p.Leu1643=
Coding: c.4927C>T
MANE Select: NM_144666
dbSNP: rs61735751
Type: single nucleotide variant
Location: chr11:6545866 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Residue 1643: a UniProt-annotated variant site (in spgf65)

Full DNHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

DNHD1-related disorder

Similar variants

DNHD1 p.Glu4486Lys Uncertain significance ★★ ⚠ same condition
DNHD1 p.His4162Leu Uncertain significance ★★ ⚠ same condition
DNHD1 p.Arg2840Gln Uncertain significance ★ ⚠ same condition
DNHD1 p.Gln895Ter Conflicting classifications of pathogenicity ★ same condition
DNHD1 p.His3335Arg Uncertain significance ★ ⚠ same condition
DNHD1 p.Ala657Ser Uncertain significance ⚠ same condition
DNHD1 p.Glu971Lys Uncertain significance ⚠ same condition
DNHD1 p.Met1535Val Uncertain significance ⚠ same condition

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/dnhd1-p-leu1643 (accessed [today's date]).

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