Is DNHD1 p.His418Tyr (c.1252C>T) pathogenic?

DNHD1 p.His418Tyr (c.1252C>T) is classified Benign in DNHD1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-02-27). AlphaMissense: likely benign (0.101); Common (popmax 36.5%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about DNHD1 p.His418Tyr (c.1252C>T)?

AlphaMissense predicts likely benign (score 0.101) — an in-silico prediction, not a clinical call.

DNHD1 p.His418Tyr

Q: How common is DNHD1 p.His418Tyr (c.1252C>T) in the general population?

DNHD1 p.His418Tyr (c.1252C>T) is common (popmax 36.5%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1252C>T · rs4758423 · VCV1272652

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.101 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 36.5%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.101	likely benign
REVEL	0.057	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.61 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.7	GERP -1.5, phastCons 0.004
Regional constraint	o/e 0.90	unconstrained · MANE · 66 kb · p 5.3e-11 · regional, not allelic
Overall
CADD	17.58	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 36.5% Admixed American · 21,889/60,014 alleles

Filtering AF 36.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 35.9%

Overall 30.7% 496,109/1,613,994 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	36.5%	3
Amishnot grpmax-eligible	34.9%	3
European (non-Finnish)	33.1%	3
Finnishnot grpmax-eligible	29.3%	3
Remaining individualsnot grpmax-eligible	28.2%	4
Middle Eastern	26.2%	4
Ashkenazi Jewishnot grpmax-eligible	24.4%	4
South Asian	22%	5
African / African-American	16.5%	6
East Asian	13%	8

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.His418Tyr
Coding: c.1252C>T
MANE Select: NM_144666
dbSNP: rs4758423
Type: single nucleotide variant
Location: chr11:6511289 (GRCh38)
Gene constraint: LOEUF 0.897 · pLI <0.01 (gnomAD)
Residue 418: a UniProt-annotated variant site (in)

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

Similar variants

DNHD1 p.Arg2928Ter Pathogenic/Likely pathogenic ★★ same type
DNHD1 p.Arg3978Ter Pathogenic/Likely pathogenic ★★ same type
DNHD1 p.Arg4048Ter Pathogenic/Likely pathogenic ★★ same type
DNHD1 p.Glu1153Ter Pathogenic/Likely pathogenic ★★ same type
DNHD1 p.Tyr2166Ter Pathogenic/Likely pathogenic ★★ same type
DNHD1 p.Arg1582Trp Uncertain significance ★★ same type
DNHD1 p.Arg1873Ser Uncertain significance ★★ ⚠ same type
DNHD1 p.Arg2555Trp 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/dnhd1-p-his418tyr (accessed [today's date]).

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