Is OFD1 p.Leu725Pro (c.2174T>C) pathogenic?

OFD1 p.Leu725Pro (c.2174T>C) is classified Likely benign in OFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely benign (0.0516); Absent from gnomAD v4.1; Associated with primary ciliary dyskinesia.

What condition is associated with OFD1 p.Leu725Pro (c.2174T>C)?

OFD1 p.Leu725Pro (c.2174T>C) is associated with primary ciliary dyskinesia (ClinVar).

How common is OFD1 p.Leu725Pro (c.2174T>C) in the general population?

OFD1 p.Leu725Pro (c.2174T>C) is absent from gnomAD v4.1 (gnomAD).

How is Primary ciliary dyskinesia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about OFD1 p.Leu725Pro (c.2174T>C)?

AlphaMissense predicts likely benign (score 0.0516) — an in-silico prediction, not a clinical call.

OFD1 p.Leu725Pro

c.2174T>C · VCV4125275

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0516 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

primary ciliary dyskinesia

Computational evidence

Protein change
AlphaMissense	0.0516	likely benign
REVEL	0.206	benign-leaning
SaProt	LLR -7.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.8	GERP -3
Regional constraint	o/e 1.02	unconstrained · MANE · 8,639 bp · p 0.77 · regional, not allelic
Overall
CADD	0.492	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: OFD1
Protein: p.Leu725Pro
Coding: c.2174T>C
MANE Select: NM_003611
Type: single nucleotide variant
Location: chrX:13760634 (GRCh38)
Structure: AlphaFold pLDDT 68.41
Residue 725: the 'mediates the interaction with sdccag8' region; the 'disordered' region

Full OFD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

primary ciliary dyskinesia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary ciliary dyskinesia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Neonatal
Prevalence: 1-5 / 10 000 (Pakistan)

Similar variants

OFD1 p.Arg909Ter Pathogenic/Likely pathogenic ★★ same condition
OFD1 p.Ala213Gly Uncertain significance ★★ ⚠ same condition
OFD1 p.Ala506Gly Uncertain significance ★★ ⚠ same condition
OFD1 p.Ala856Val Uncertain significance ★★ ⚠ same condition
OFD1 p.Arg263Trp Uncertain significance ★★ ⚠ same condition
OFD1 p.Arg467Ser Uncertain significance ★★ ⚠ same condition
OFD1 p.Arg487Trp Uncertain significance ★★ ⚠ same condition
OFD1 p.Asn118Thr 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/ofd1-p-leu725pro (accessed [today's date]).

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