Is DNAH3 p.Ala2446= (c.7338C>T) pathogenic?

DNAH3 p.Ala2446= (c.7338C>T) is classified Likely benign in DNAH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-01). Rare (popmax 0.582%, nfe).

How common is DNAH3 p.Ala2446= (c.7338C>T) in the general population?

DNAH3 p.Ala2446= (c.7338C>T) is rare (popmax 0.582%, nfe) (gnomAD).

DNAH3 p.Ala2446=

c.7338C>T · rs149829197 · VCV2646295

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.582%, nfe)

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 -3.5	GERP -5.8
Overall
CADD	0.141	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.582% European (non-Finnish) · 6,863/1,180,028 alleles

Filtering AF 0.57% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.565%

Overall 0.492% 7,938/1,614,106 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.02%	98
European (non-Finnish)grpmax	0.582%	172
Remaining individualsnot grpmax-eligible	0.435%	230
African / African-American	0.0707%	1,415
South Asian	0.0582%	1,718
Admixed American	0.045%	2,223
Ashkenazi Jewishnot grpmax-eligible	0.0372%	2,691
Middle Eastern	0.0165%	6,062
East Asian	0.00446%	22,436

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: DNAH3
Protein: p.Ala2446=
Coding: c.7338C>T
MANE Select: NM_001347886
dbSNP: rs149829197
Type: single nucleotide variant
Location: chr16:20985266 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 (gnomAD)
Residue 2446: a UniProt-annotated variant site (found in a male with oligoasthenoteratozoospermia; uncertain significance; severely impaired sperm motility; multiple morphological abnormalities of the sperm flagella; partial loss and disintegration of the flagellar axoneme, accompanied by damage to the mitochondrial sheath); a UniProt-annotated variant site (found in a male with asthenoteratozoospermia; uncertain significance; severely impaired sperm motility; multiple morphological abnormalities of the sperm flagella; disorganization of flagellar components, notably inner dynein arms); the 'aaa 4' region

Full DNAH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAH3 p.Ala2446Ser Uncertain significance ★ ⚠ same residue
DNAH3 p.Ala1918Gly Uncertain significance ★★ ⚠ same type
DNAH3 p.Arg1228Gln Uncertain significance ★★ same type
DNAH3 p.Arg635Gln Uncertain significance ★★ same type
DNAH3 p.Asn1728Ser Uncertain significance ★★ ⚠ same type
DNAH3 p.Asp3656Asn Uncertain significance ★★ same type
DNAH3 p.Leu2597Val Uncertain significance ★★ same type
DNAH3 p.Leu4044Phe 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/dnah3-p-ala2446 (accessed [today's date]).

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