Is DNAH2 p.Arg4255Gln (c.12764G>A) pathogenic?

DNAH2 p.Arg4255Gln (c.12764G>A) is classified Benign in DNAH2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-02-28). AlphaMissense: likely benign (0.205); Common (popmax 23.9%, amr) — too common for a highly-penetrant pathogenic allele; Associated with DNAH2-related disorder.

What condition is associated with DNAH2 p.Arg4255Gln (c.12764G>A)?

DNAH2 p.Arg4255Gln (c.12764G>A) is associated with DNAH2-related disorder (ClinVar).

What do computational predictors say about DNAH2 p.Arg4255Gln (c.12764G>A)?

AlphaMissense predicts likely benign (score 0.205) — an in-silico prediction, not a clinical call.

DNAH2 p.Arg4255Gln

Q: How common is DNAH2 p.Arg4255Gln (c.12764G>A) in the general population?

DNAH2 p.Arg4255Gln (c.12764G>A) is common (popmax 23.9%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.12764G>A · rs61745181 · VCV3059186

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.205 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 23.9%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

DNAH2-related disorder

Computational evidence

Protein change
AlphaMissense	0.205	likely benign
REVEL	0.142	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 35 kb · p 4.5e-10 · regional, not allelic
Overall
CADD	32.0	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 23.9% Admixed American · 14,331/60,004 alleles

Filtering AF 23.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 23.4%

Overall 8.95% 144,402/1,614,054 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	23.9%	4
East Asian	16.9%	6
South Asian	16.7%	6
Remaining individualsnot grpmax-eligible	9.03%	11
Amishnot grpmax-eligible	8.66%	12
Finnishnot grpmax-eligible	8.1%	12
European (non-Finnish)	7.89%	13
Ashkenazi Jewishnot grpmax-eligible	5.61%	18
Middle Eastern	4.42%	23
African / African-American	1.72%	58

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.Arg4255Gln
Coding: c.12764G>A
MANE Select: NM_020877
dbSNP: rs61745181
Type: single nucleotide variant
Location: chr17:7832616 (GRCh38)
Gene constraint: LOEUF 0.655 · pLI <0.01 (gnomAD)
Residue 4255: 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

DNAH2-related disorder

Similar variants

DNAH2 p.Arg1633Gly Uncertain significance ⚠ same condition
DNAH2 c.11478+4G>A Benign same condition
DNAH2 c.1171-715G>A Likely benign same condition
DNAH2 c.1377-9C>A Likely benign same condition
DNAH2 c.1904+123T>C Benign same condition
DNAH2 c.1904+136C>T Likely benign same condition
DNAH2 c.1904+345A>G Likely benign same condition
DNAH2 c.3179+4C>T Likely benign 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-arg4255gln (accessed [today's date]).

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