Is HYDIN p.Lys1125Met (c.3374A>T) pathogenic?

HYDIN p.Lys1125Met (c.3374A>T) is classified Likely benign in HYDIN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-01). AlphaMissense: likely benign (0.1971); Low-frequency (popmax 2.85%, afr).

How common is HYDIN p.Lys1125Met (c.3374A>T) in the general population?

HYDIN p.Lys1125Met (c.3374A>T) is low-frequency (popmax 2.85%, afr) (gnomAD).

What do computational predictors say about HYDIN p.Lys1125Met (c.3374A>T)?

AlphaMissense predicts likely benign (score 0.1971) — an in-silico prediction, not a clinical call.

HYDIN p.Lys1125Met

c.3374A>T · rs79123258 · VCV2646780

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1971 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.85%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1971	likely benign
REVEL	0.264	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	Δ0.23	acceptor gain · deltas
Pangolin	Δ0.30	gain · loss 0.21 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.9	GERP 3.5, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 9,264 bp · p 0.032 · regional, not allelic
Overall
CADD	23.0	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 2.85% African / African-American · 1,019/35,780 alleles

Filtering AF 2.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.64%

Overall 0.255% 1,113/437,290 alleles · low-frequency exomes 162/310,340 · genomes 951/126,950 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.85%	35
Admixed American	0.179%	558
Remaining individualsnot grpmax-eligible	0.144%	696
Middle Eastern	0.0483%	2,072
Ashkenazi Jewishnot grpmax-eligible	0.0368%	2,715
European (non-Finnish)	0.00666%	15,022
South Asian	0.00475%	21,038

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.Lys1125Met
Coding: c.3374A>T
MANE Select: NM_001270974
dbSNP: rs79123258
Type: single nucleotide variant
Location: chr16:71018399 (GRCh38)
Gene constraint: LOEUF 0.555 · pLI <0.01 (gnomAD)
Residue 1125: a UniProt-annotated variant site (in cild5; uncertain significance)

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-lys1125met (accessed [today's date]).

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