Is DNAH1 p.Ile2226Val (c.6676A>G) pathogenic?

DNAH1 p.Ile2226Val (c.6676A>G) is classified Benign/Likely benign in DNAH1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0631); Rare (popmax 0.797%, nfe); Associated with spermatogenic failure 18.

What condition is associated with DNAH1 p.Ile2226Val (c.6676A>G)?

DNAH1 p.Ile2226Val (c.6676A>G) is associated with spermatogenic failure 18, ciliary dyskinesia, primary, 37 (ClinVar).

How common is DNAH1 p.Ile2226Val (c.6676A>G) in the general population?

DNAH1 p.Ile2226Val (c.6676A>G) is rare (popmax 0.797%, nfe) (gnomAD).

What do computational predictors say about DNAH1 p.Ile2226Val (c.6676A>G)?

AlphaMissense predicts likely benign (score 0.0631) — an in-silico prediction, not a clinical call.

DNAH1 p.Ile2226Val

c.6676A>G · rs112505934 · VCV478481

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0631 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.797%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

spermatogenic failure 18

Computational evidence

Protein change
AlphaMissense	0.0631	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.42 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.019	GERP -3.8
Regional constraint	o/e 0.86	unconstrained · MANE · 42 kb · p 1.9e-16 · regional, not allelic
Overall
CADD	8.645	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.797% European (non-Finnish) · 9,398/1,179,842 alleles

Filtering AF 0.783% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.778%

Overall 0.696% 11,237/1,613,864 alleles · rare exomes 10,433/1,461,570 · genomes 804/152,294 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	4.29%	23
European (non-Finnish)grpmax	0.797%	126
Remaining individualsnot grpmax-eligible	0.706%	142
Finnishnot grpmax-eligible	0.624%	160
Ashkenazi Jewishnot grpmax-eligible	0.622%	161
South Asian	0.573%	174
Middle Eastern	0.314%	319
Admixed American	0.245%	408
African / African-American	0.116%	862
East Asian	0.00223%	44,882

Amish 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: DNAH1
Protein: p.Ile2226Val
Coding: c.6676A>G
MANE Select: NM_015512
dbSNP: rs112505934
Type: single nucleotide variant
Location: chr3:52372236 (GRCh38)
Gene constraint: LOEUF 0.759 · pLI <0.01 (gnomAD)
Residue 2226: a UniProt-annotated variant site (in spgf18); the 'aaa 3' region

Full DNAH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

spermatogenic failure 18 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ciliary dyskinesia, primary, 37

Similar variants

DNAH1 p.Ile2226Thr Uncertain significance ★ ⚠ same residue
DNAH1 c.1034-2A>G Likely pathogenic ★★ same condition
DNAH1 c.10474+1G>A Pathogenic/Likely pathogenic ★★ same condition
DNAH1 c.10968+2C>T Likely pathogenic ★★ same condition
DNAH1 c.5244+1G>A Likely pathogenic ★★ same condition
DNAH1 p.Arg1702Ter Pathogenic ★★ same condition
DNAH1 p.Arg2479Ter Pathogenic/Likely pathogenic ★★ same condition
DNAH1 p.Arg2622Ter 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/dnah1-p-ile2226val (accessed [today's date]).

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