Is MPO p.Val286Phe (c.856G>T) pathogenic?

MPO p.Val286Phe (c.856G>T) is classified Uncertain significance in MPO (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-16). AlphaMissense: likely benign (0.0908); Ultra-rare (popmax 0.0179%, nfe).

How common is MPO p.Val286Phe (c.856G>T) in the general population?

MPO p.Val286Phe (c.856G>T) is ultra-rare (popmax 0.0179%, nfe) (gnomAD).

What do computational predictors say about MPO p.Val286Phe (c.856G>T)?

AlphaMissense predicts likely benign (score 0.0908) — an in-silico prediction, not a clinical call.

MPO p.Val286Phe

c.856G>T · rs372446639 · VCV2364428

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0908 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0908	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -2.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.4	GERP -4.7
Regional constraint	o/e 0.96	unconstrained · MANE · 10 kb · p 0.18 · regional, not allelic
Overall
CADD	15.9	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0179% European (non-Finnish) · 211/1,179,522 alleles

Filtering AF 0.0159% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.0141% 228/1,611,814 alleles · ultra-rare exomes 211/1,459,582 · genomes 17/152,232 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0179%	5,590
African / African-American	0.0107%	9,366
Finnishnot grpmax-eligible	0.00635%	15,745
Admixed American	0.00501%	19,945
Remaining individualsnot grpmax-eligible	0.00321%	31,183

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: MPO
Protein: p.Val286Phe
Coding: c.856G>T
MANE Select: NM_000250
dbSNP: rs372446639
Type: single nucleotide variant
Location: chr17:58279037 (GRCh38)
Gene constraint: LOEUF 0.992 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.55 · 49 PDB

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

Similar variants

MPO p.Gln241Ter Pathogenic/Likely pathogenic ★★ same type
MPO p.Trp602Ter Likely pathogenic ★★ same type
MPO p.Arg691Gln Uncertain significance ★★ ⚠ same type
MPO p.Met356Val Uncertain significance ★★ ⚠ same type
MPO c.2031-6A>C Benign ★★ same type
MPO p.Arg604Cys Likely benign ★★ ⚠ same type
MPO p.Asn729= Benign/Likely benign ★★ same type
MPO p.Pro105= Likely benign ★★ 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/mpo-p-val286phe (accessed [today's date]).

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