Is DNAH3 p.Phe1693Leu (c.5077T>C) pathogenic?

DNAH3 p.Phe1693Leu (c.5077T>C) is classified Uncertain significance in DNAH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-02). AlphaMissense: likely pathogenic (0.7364); Ultra-rare (popmax 0.0404%, nfe).

How common is DNAH3 p.Phe1693Leu (c.5077T>C) in the general population?

DNAH3 p.Phe1693Leu (c.5077T>C) is ultra-rare (popmax 0.0404%, nfe) (gnomAD).

What do computational predictors say about DNAH3 p.Phe1693Leu (c.5077T>C)?

AlphaMissense predicts likely pathogenic (score 0.7364) — an in-silico prediction, not a clinical call.

DNAH3 p.Phe1693Leu

c.5077T>C · rs201066816 · VCV3083922

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7364 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0404%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.7364	likely pathogenic
REVEL	0.119	moderately benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 2.7, phastCons 1
Overall
CADD	23.1	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 F1739L vs ClinVar F1693L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0404% European (non-Finnish) · 477/1,179,998 alleles

Filtering AF 0.0374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0362%

Overall 0.0335% 540/1,613,884 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0625%	1,600
European (non-Finnish)grpmax	0.0404%	2,474
Remaining individualsnot grpmax-eligible	0.0224%	4,463
African / African-American	0.00534%	18,711
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
South Asian	0.00329%	30,360
Admixed American	0.00167%	59,984

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.Phe1693Leu
Coding: c.5077T>C
MANE Select: NM_001347886
dbSNP: rs201066816
Type: single nucleotide variant
Location: chr16:21031269 (GRCh38)
Gene constraint: LOEUF 0.834 · pLI <0.01 (gnomAD)
Residue 1693: 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); the 'aaa 2' region

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

Similar variants

DNAH3 p.Phe1693Ile 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-phe1693leu (accessed [today's date]).

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