Is DNAH2 p.Arg4055Trp (c.12163C>T) pathogenic?

DNAH2 p.Arg4055Trp (c.12163C>T) is classified Uncertain significance in DNAH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-15). AlphaMissense: ambiguous (0.3557); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with DNAH2 p.Arg4055Trp (c.12163C>T)?

DNAH2 p.Arg4055Trp (c.12163C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DNAH2 p.Arg4055Trp (c.12163C>T) in the general population?

DNAH2 p.Arg4055Trp (c.12163C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about DNAH2 p.Arg4055Trp (c.12163C>T)?

AlphaMissense predicts ambiguous (score 0.3557) — an in-silico prediction, not a clinical call.

DNAH2 p.Arg4055Trp

c.12163C>T · rs534253033 · VCV2349055

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3557 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3557	ambiguous
REVEL	0.461	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.017	GERP -0.69, phastCons 0.004
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 4.5e-10 · regional, not allelic
Overall
CADD	24.6	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.00359% 58/1,614,086 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
South Asian	0.00659%	15,180
Remaining individualsnot grpmax-eligible	0.0064%	15,627
European (non-Finnish)	0.00373%	26,819
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
East Asian	0.00223%	44,884
African / African-American	0.00133%	75,024

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: DNAH2
Protein: p.Arg4055Trp
Coding: c.12163C>T
MANE Select: NM_020877
dbSNP: rs534253033
Type: single nucleotide variant
Location: chr17:7830775 (GRCh38)
Gene constraint: LOEUF 0.655 · pLI <0.01 (gnomAD)
Residue 4055: a UniProt-annotated variant site (in spgf45; decreased protein abundance; loss of inner dynein arm assembly; in spermatozoa from patients)

Full DNAH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNAH2 p.Arg4055Gln Uncertain significance ★ same residue
DNAH2 p.Ala1036Val Uncertain significance ★★ ⚠ same condition
DNAH2 p.Arg1533Cys Uncertain significance ★★ ⚠ same condition
DNAH2 p.Arg2538Gln Uncertain significance ★★ same condition
DNAH2 p.Arg3759His Uncertain significance ★★ ⚠ same condition
DNAH2 p.Gln2069Glu Uncertain significance ★★ same condition
DNAH2 p.Ile4043Ser Uncertain significance ★★ ⚠ same condition
DNAH2 p.Pro3819Leu 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/dnah2-p-arg4055trp (accessed [today's date]).

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