Is HYDIN p.Pro549Ser (c.1645C>T) pathogenic?

HYDIN p.Pro549Ser (c.1645C>T) is classified Uncertain significance in HYDIN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-09). AlphaMissense: likely benign (0.2858); Rare (popmax 0.225%, afr); Associated with Inborn genetic diseases.

What condition is associated with HYDIN p.Pro549Ser (c.1645C>T)?

HYDIN p.Pro549Ser (c.1645C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HYDIN p.Pro549Ser (c.1645C>T) in the general population?

HYDIN p.Pro549Ser (c.1645C>T) is rare (popmax 0.225%, afr) (gnomAD).

What do computational predictors say about HYDIN p.Pro549Ser (c.1645C>T)?

AlphaMissense predicts likely benign (score 0.2858) — an in-silico prediction, not a clinical call.

HYDIN p.Pro549Ser

c.1645C>T · rs556017609 · VCV2269023

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2858 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.225%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2858	likely benign
REVEL	0.166	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 7.6	GERP 3.7, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 73 kb · p 7.8e-09 · regional, not allelic
Overall
CADD	22.3	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 0.225% African / African-American · 88/39,080 alleles

Filtering AF 0.187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.173%

Overall 0.0196% 106/541,502 alleles · rare exomes 34/438,566 · genomes 72/102,936 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.225%	444
Middle Eastern	0.0465%	2,150
Admixed American	0.0412%	2,425
Remaining individualsnot grpmax-eligible	0.015%	6,677
European (non-Finnish)	0.000646%	154,857

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.Pro549Ser
Coding: c.1645C>T
MANE Select: NM_001270974
dbSNP: rs556017609
Type: single nucleotide variant
Location: chr16:71088326 (GRCh38)
Gene constraint: LOEUF 0.555 · pLI <0.01 (gnomAD)
Residue 549: the 'interaction with kif9' region; 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.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
HYDIN p.Pro2991Thr 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-pro549ser (accessed [today's date]).

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