Is HYDIN p.Pro4538= (c.13614C>G) pathogenic?

HYDIN p.Pro4538= (c.13614C>G) is classified Likely benign in HYDIN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-01). Rare (popmax 0.616%, nfe).

How common is HYDIN p.Pro4538= (c.13614C>G) in the general population?

HYDIN p.Pro4538= (c.13614C>G) is rare (popmax 0.616%, nfe) (gnomAD).

HYDIN p.Pro4538=

c.13614C>G · rs202133666 · VCV2646697

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.616%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.9	GERP -3.5
Overall
CADD	0.174	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.616% European (non-Finnish) · 7,262/1,179,720 alleles

Filtering AF 0.604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.599%

Overall 0.528% 8,518/1,613,252 alleles · rare exomes 7,972/1,461,078 · genomes 546/152,174 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.34%	74
European (non-Finnish)grpmax	0.616%	162
Remaining individualsnot grpmax-eligible	0.544%	184
Amishnot grpmax-eligible	0.439%	228
Admixed American	0.382%	262
Middle Eastern	0.302%	331
South Asian	0.164%	611
African / African-American	0.0867%	1,154
Finnishnot grpmax-eligible	0.083%	1,205

Ashkenazi Jewish 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: HYDIN
Protein: p.Pro4538=
Coding: c.13614C>G
MANE Select: NM_001270974
dbSNP: rs202133666
Type: single nucleotide variant
Location: chr16:70833952 (GRCh38)
Gene constraint: LOEUF 0.555 · pLI <0.01 (gnomAD)
Residue 4538: 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

Similar variants

HYDIN c.12444-1G>A Likely pathogenic ★★ same type
HYDIN c.12444-3C>G Likely pathogenic ★★ same type
HYDIN c.6669+1G>A Likely pathogenic ★★ same type
HYDIN p.Arg2120Ter Likely pathogenic ★★ same type
HYDIN p.Arg444Ter Pathogenic/Likely pathogenic ★★ same type
HYDIN p.Glu683Ter Pathogenic/Likely pathogenic ★★ same type
HYDIN p.Tyr599Ter Pathogenic/Likely pathogenic ★★ same type
HYDIN p.Arg163Gln 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/hydin-p-pro4538 (accessed [today's date]).

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