Is MCM8 p.His161Pro (c.482A>C) pathogenic?

MCM8 p.His161Pro (c.482A>C) is classified Likely pathogenic in MCM8 (ClinVar, Single submitter, 2 submitters). AlphaMissense: likely pathogenic (0.9842); Very rare (popmax 8.48e-05%, nfe); Associated with premature ovarian failure 10.

What condition is associated with MCM8 p.His161Pro (c.482A>C)?

MCM8 p.His161Pro (c.482A>C) is associated with premature ovarian failure 10, azoospermia (ClinVar).

How common is MCM8 p.His161Pro (c.482A>C) in the general population?

MCM8 p.His161Pro (c.482A>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about MCM8 p.His161Pro (c.482A>C)?

AlphaMissense predicts likely pathogenic (score 0.9842) — an in-silico prediction, not a clinical call.

MCM8 p.His161Pro

c.482A>C · rs140044814 · VCV1328959

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9842 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

premature ovarian failure 10

Computational evidence

Protein change
AlphaMissense	0.9842	likely pathogenic ✓ concordant with ClinVar · top 8% in MCM8
REVEL	0.555	indeterminate
SaProt	LLR -14.92	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 42 kb · p 0.14 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,440 alleles

Overall 6.2e-05% 1/1,612,016 alleles · very rare exomes 1/1,459,646 · genomes 0/152,370 · 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: MCM8
Protein: p.His161Pro
Coding: c.482A>C
MANE Select: NM_032485
dbSNP: rs140044814
Type: single nucleotide variant
Location: chr20:5955247 (GRCh38)
Gene constraint: LOEUF 0.97 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.55 · 7 PDB
Residue 161: an α-helix

Full MCM8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

premature ovarian failure 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: azoospermia

Similar variants

MCM8 p.Arg309Ter Pathogenic ★ same condition
MCM8 p.Cys468Ter Likely pathogenic ★ same condition
MCM8 p.Tyr435Ter Likely pathogenic ★ same condition
MCM8 p.Arg345Ter Conflicting classifications of pathogenicity ★ same condition
MCM8 p.Gly45Glu Uncertain significance ★ ⚠ same condition
MCM8 p.Ile444Val Uncertain significance ★ ⚠ same condition
MCM8 p.Lys30Thr Uncertain significance ★ ⚠ same condition
MCM8 c.1953+1G>C Likely pathogenic 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/mcm8-p-his161pro (accessed [today's date]).

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