Is DNAH8 p.Leu4034Phe (c.12100C>T) pathogenic?

DNAH8 p.Leu4034Phe (c.12100C>T) is classified Conflicting classifications of pathogenicity in DNAH8 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-01). AlphaMissense: ambiguous (0.3623); Rare (popmax 0.154%, nfe); Associated with primary ciliary dyskinesia.

What condition is associated with DNAH8 p.Leu4034Phe (c.12100C>T)?

DNAH8 p.Leu4034Phe (c.12100C>T) is associated with primary ciliary dyskinesia (ClinVar).

How common is DNAH8 p.Leu4034Phe (c.12100C>T) in the general population?

DNAH8 p.Leu4034Phe (c.12100C>T) is rare (popmax 0.154%, nfe) (gnomAD).

How is Primary ciliary dyskinesia inherited?

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

What do computational predictors say about DNAH8 p.Leu4034Phe (c.12100C>T)?

AlphaMissense predicts ambiguous (score 0.3623) — an in-silico prediction, not a clinical call.

DNAH8 p.Leu4034Phe

c.12100C>T · rs146505940 · VCV525268

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.3623 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.154%, nfe)

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.3623	ambiguous
REVEL	0.225	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 112 kb · p 0.0022 · regional, not allelic
Overall
CADD	24.7	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 L3817F vs ClinVar L4034F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.154% European (non-Finnish) · 1,813/1,180,004 alleles

Filtering AF 0.148% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.145%

Overall 0.123% 1,980/1,614,136 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.178%	562
European (non-Finnish)grpmax	0.154%	651
Remaining individualsnot grpmax-eligible	0.064%	1,563
African / African-American	0.0133%	7,504
Admixed American	0.00333%	30,011
South Asian	0.0011%	91,080

Finnish 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: DNAH8
Protein: p.Leu4034Phe
Coding: c.12100C>T
MANE Select: NM_001206927
dbSNP: rs146505940
Type: single nucleotide variant
Location: chr6:38945559 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI <0.01 (gnomAD)
Residue 4034: a UniProt-annotated variant site (found in a patient with primary ciliary dyskinesia; uncertain significance); the 'aaa 6' region

Full DNAH8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary ciliary dyskinesia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary ciliary dyskinesia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Neonatal
Prevalence: 1-5 / 10 000 (Pakistan)

Similar variants

DNAH8 c.10963-1G>A Likely pathogenic ★★ same condition
DNAH8 c.11563+1G>T Likely pathogenic ★★ same condition
DNAH8 c.2664+2T>C Likely pathogenic ★★ same condition
DNAH8 c.5734-1G>T Likely pathogenic ★★ same condition
DNAH8 p.Arg1090Ter Pathogenic/Likely pathogenic ★★ same condition
DNAH8 p.Arg207Ter Pathogenic/Likely pathogenic ★★ same condition
DNAH8 p.Arg2878Ter Pathogenic ★★ same condition
DNAH8 p.Arg4166Ter Pathogenic/Likely pathogenic ★★ 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/dnah8-p-leu4034phe (accessed [today's date]).

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