Is HYDIN p.Pro4535Ser (c.13603C>T) pathogenic?

HYDIN p.Pro4535Ser (c.13603C>T) is classified Uncertain significance in HYDIN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-01). AlphaMissense: likely benign (0.1109); Ultra-rare (popmax 0.0802%, sas); Associated with primary ciliary dyskinesia 5.

What condition is associated with HYDIN p.Pro4535Ser (c.13603C>T)?

HYDIN p.Pro4535Ser (c.13603C>T) is associated with primary ciliary dyskinesia 5 (ClinVar).

How common is HYDIN p.Pro4535Ser (c.13603C>T) in the general population?

HYDIN p.Pro4535Ser (c.13603C>T) is ultra-rare (popmax 0.0802%, sas) (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 HYDIN p.Pro4535Ser (c.13603C>T)?

AlphaMissense predicts likely benign (score 0.1109) — an in-silico prediction, not a clinical call.

HYDIN p.Pro4535Ser

c.13603C>T · rs267604614 · VCV2671702

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1109 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0802%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

primary ciliary dyskinesia 5

Computational evidence

Protein change
AlphaMissense	0.1109	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.71	GERP -2.7, phastCons 0.86
Regional constraint	o/e 0.64	unconstrained · MANE · 4,365 bp · p 5.5e-08 · regional, not allelic
Overall
CADD	7.526	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0802% South Asian · 73/91,014 alleles

Filtering AF 0.0654% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0599%

Overall 0.00707% 114/1,613,220 alleles · ultra-rare exomes 107/1,461,080 · genomes 7/152,140 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0802%	1,247
Middle Eastern	0.0501%	1,997
Admixed American	0.015%	6,661
Remaining individualsnot grpmax-eligible	0.0144%	6,937
European (non-Finnish)	0.0017%	58,983

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: HYDIN
Protein: p.Pro4535Ser
Coding: c.13603C>T
MANE Select: NM_001270974
dbSNP: rs267604614
Type: single nucleotide variant
Location: chr16:70833963 (GRCh38)
Gene constraint: LOEUF 0.555 · pLI <0.01 (gnomAD)
Residue 4535: a UniProt-annotated variant site (in cild5; uncertain significance); a UniProt-annotated variant site (in cild5; likely pathogenic; absence of spef2 in ciliary axonemes of respiratory cells)

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

Disease context

primary ciliary dyskinesia 5 — 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

HYDIN c.12444-1G>A Likely pathogenic ★★ same condition
HYDIN c.12444-3C>G Likely pathogenic ★★ same condition
HYDIN c.6669+1G>A Likely pathogenic ★★ same condition
HYDIN p.Arg2120Ter Likely pathogenic ★★ same condition
HYDIN p.Arg444Ter Pathogenic/Likely pathogenic ★★ same condition
HYDIN p.Glu683Ter Pathogenic/Likely pathogenic ★★ same condition
HYDIN p.Arg163Gln Uncertain significance ★★ ⚠ same condition
HYDIN p.Arg2931Cys 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/hydin-p-pro4535ser (accessed [today's date]).

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