Is MCM9 p.Phe154Ser (c.461T>C) pathogenic?

MCM9 p.Phe154Ser (c.461T>C) is classified Uncertain significance in MCM9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely pathogenic (0.6779); Ultra-rare (popmax 0.0213%, afr); Associated with Inborn genetic diseases.

What condition is associated with MCM9 p.Phe154Ser (c.461T>C)?

MCM9 p.Phe154Ser (c.461T>C) is associated with Inborn genetic diseases (ClinVar).

How common is MCM9 p.Phe154Ser (c.461T>C) in the general population?

MCM9 p.Phe154Ser (c.461T>C) is ultra-rare (popmax 0.0213%, afr) (gnomAD).

What do computational predictors say about MCM9 p.Phe154Ser (c.461T>C)?

AlphaMissense predicts likely pathogenic (score 0.6779) — an in-silico prediction, not a clinical call.

MCM9 p.Phe154Ser

c.461T>C · VCV4052716

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6779 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0213%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6779	likely pathogenic
REVEL	0.567	indeterminate
SaProt	LLR -10.94	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 117 kb · p 0.0083 · regional, not allelic
Overall
CADD	25.8	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 0.0213% African / African-American · 16/74,950 alleles

Filtering AF 0.0133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.00112% 18/1,614,116 alleles · ultra-rare exomes 9/1,461,886 · genomes 9/152,230 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0213%	4,684
Admixed American	0.00167%	60,004
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: MCM9
Protein: p.Phe154Ser
Coding: c.461T>C
MANE Select: NM_017696
Type: single nucleotide variant
Location: chr6:118923971 (GRCh38)
Gene constraint: LOEUF 0.916 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.24 · 6 PDB
Residue 154: a β-strand

Full MCM9 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

MCM9 p.Ala812Thr Uncertain significance ★★ ⚠ same condition
MCM9 p.Arg168Gln Uncertain significance ★★ ⚠ same condition
MCM9 p.Asp298Asn Uncertain significance ★★ ⚠ same condition
MCM9 p.Ala158Thr Uncertain significance ★ same condition
MCM9 p.Ala400Ser Uncertain significance ★ ⚠ same condition
MCM9 p.Ala456Val Uncertain significance ★ ⚠ same condition
MCM9 p.Ala561Thr Uncertain significance ★ ⚠ same condition
MCM9 p.Ala593Thr 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/mcm9-p-phe154ser (accessed [today's date]).

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