Is HYDIN p.Ala506Pro (c.1516G>C) pathogenic?

HYDIN p.Ala506Pro (c.1516G>C) is classified Uncertain significance in HYDIN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: ambiguous (0.3958); Very rare (popmax 0.00119%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HYDIN p.Ala506Pro (c.1516G>C)?

HYDIN p.Ala506Pro (c.1516G>C) is associated with Inborn genetic diseases (ClinVar).

How common is HYDIN p.Ala506Pro (c.1516G>C) in the general population?

HYDIN p.Ala506Pro (c.1516G>C) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about HYDIN p.Ala506Pro (c.1516G>C)?

AlphaMissense predicts ambiguous (score 0.3958) — an in-silico prediction, not a clinical call.

HYDIN p.Ala506Pro

c.1516G>C · VCV4273097

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3958 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3958	ambiguous
REVEL	0.139	moderately benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.43	GERP 1.9
Regional constraint	o/e 0.60	unconstrained · MANE · 73 kb · p 7.8e-09 · regional, not allelic
Overall
CADD	18.64	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 0.00119% European (non-Finnish) · 4/335,974 alleles

Filtering AF 0.000378% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000188%

Overall 0.000665% 4/601,434 alleles · very rare exomes 4/469,720 · genomes 0/131,714 · joint denominator

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.Ala506Pro
Coding: c.1516G>C
MANE Select: NM_001270974
Type: single nucleotide variant
Location: chr16:71088455 (GRCh38)
Gene constraint: LOEUF 0.555 · pLI <0.01 (gnomAD)
Residue 506: the 'interaction with kif9' region; an α-helix; a UniProt-annotated variant site (in cild5; uncertain significance)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HYDIN p.Ala506Asp Uncertain significance ★ ⚠ same residue
HYDIN p.Arg5Ile Uncertain significance ★★ ⚠ same condition
HYDIN p.Arg777Gly Uncertain significance ★★ ⚠ same condition
HYDIN p.Asn125Tyr Uncertain significance ★★ ⚠ same condition
HYDIN p.Asn2915Ser Uncertain significance ★★ ⚠ same condition
HYDIN p.Asn387His Uncertain significance ★★ ⚠ same condition
HYDIN p.Glu410Ala Uncertain significance ★★ ⚠ same condition
HYDIN p.Gly681Arg 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-ala506pro (accessed [today's date]).

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