Is MCM8 p.Phe591Ser (c.1772T>C) pathogenic?

MCM8 p.Phe591Ser (c.1772T>C) is classified Uncertain significance in MCM8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-21). AlphaMissense: likely pathogenic (0.9886); Ultra-rare (popmax 0.0364%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MCM8 p.Phe591Ser (c.1772T>C)?

MCM8 p.Phe591Ser (c.1772T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MCM8 p.Phe591Ser (c.1772T>C) in the general population?

MCM8 p.Phe591Ser (c.1772T>C) is ultra-rare (popmax 0.0364%, nfe) (gnomAD).

What do computational predictors say about MCM8 p.Phe591Ser (c.1772T>C)?

AlphaMissense predicts likely pathogenic (score 0.9886) — an in-silico prediction, not a clinical call.

MCM8 p.Phe591Ser

c.1772T>C · rs61752030 · VCV2368490

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9886 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0364%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9886	likely pathogenic · top 7% in MCM8
REVEL	0.62	indeterminate
SaProt	LLR -13.12	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.50 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 42 kb · p 0.14 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0364% European (non-Finnish) · 429/1,179,922 alleles

Filtering AF 0.0335% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0323%

Overall 0.0287% 463/1,613,940 alleles · ultra-rare exomes 433/1,461,730 · genomes 30/152,210 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0384%	2,604
European (non-Finnish)grpmax	0.0364%	2,750
African / African-American	0.012%	8,325
Finnishnot grpmax-eligible	0.00156%	64,038

Remaining individuals 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: MCM8
Protein: p.Phe591Ser
Coding: c.1772T>C
MANE Select: NM_032485
dbSNP: rs61752030
Type: single nucleotide variant
Location: chr20:5984819 (GRCh38)
Gene constraint: LOEUF 0.97 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.55 · 7 PDB
Residue 591: the mcm c-terminal aaa(+) atpase domain

Full MCM8 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

MCM8 p.Ala172Val Uncertain significance ★ ⚠ same condition
MCM8 p.Ala244Pro Uncertain significance ★ ⚠ same condition
MCM8 p.Ala436Pro Uncertain significance ★ ⚠ same condition
MCM8 p.Ala504Val Uncertain significance ★ ⚠ same condition
MCM8 p.Ala529Thr Uncertain significance ★ same condition
MCM8 p.Ala776Val Uncertain significance ★ ⚠ same condition
MCM8 p.Ala812Asp Uncertain significance ★ ⚠ same condition
MCM8 p.Arg227His 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/mcm8-p-phe591ser (accessed [today's date]).

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