Is MPEG1 p.Pro405Thr (c.1213C>A) pathogenic?

MPEG1 p.Pro405Thr (c.1213C>A) is classified Conflicting classifications of pathogenicity in MPEG1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.1797); Rare (popmax 0.501%, nfe); Associated with immunodeficiency 77.

What condition is associated with MPEG1 p.Pro405Thr (c.1213C>A)?

MPEG1 p.Pro405Thr (c.1213C>A) is associated with immunodeficiency 77 (ClinVar).

How common is MPEG1 p.Pro405Thr (c.1213C>A) in the general population?

MPEG1 p.Pro405Thr (c.1213C>A) is rare (popmax 0.501%, nfe) (gnomAD).

What do computational predictors say about MPEG1 p.Pro405Thr (c.1213C>A)?

AlphaMissense predicts likely benign (score 0.1797) — an in-silico prediction, not a clinical call.

MPEG1 p.Pro405Thr

c.1213C>A · rs200420254 · VCV1035590

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1797 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.501%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

immunodeficiency 77

Computational evidence

Protein change
AlphaMissense	0.1797	likely benign
REVEL	0.291	indeterminate
SaProt	LLR -9.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 2,147 bp · p 0.89 · regional, not allelic
Overall
CADD	25.3	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 0.501% European (non-Finnish) · 5,911/1,180,012 alleles

Filtering AF 0.49% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.486%

Overall 0.379% 6,114/1,614,158 alleles · rare exomes 5,785/1,461,884 · genomes 329/152,274 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.501%	200
Remaining individualsnot grpmax-eligible	0.182%	548
African / African-American	0.068%	1,471
Admixed American	0.0366%	2,729
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,922
Finnishnot grpmax-eligible	0.0156%	6,402
South Asian	0.0011%	91,084

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: MPEG1
Protein: p.Pro405Thr
Coding: c.1213C>A
MANE Select: NM_001039396
dbSNP: rs200420254
Type: single nucleotide variant
Location: chr11:59211653 (GRCh38)
Gene constraint: LOEUF 1.941 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 83.22 · 5 PDB
Residue 405: a UniProt-annotated variant site (in imd77; decreased defense response to bacterium); a UniProt-annotated variant site (in imd77; uncertain significance; decreased defense response to bacterium); a turn

Full MPEG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

immunodeficiency 77 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MPEG1 p.Ala525Val Uncertain significance ★★ ⚠ same condition
MPEG1 p.His420Tyr Uncertain significance ★★ ⚠ same condition
MPEG1 p.Thr73Ala Likely benign ★★ same condition
MPEG1 p.Asn249Ser Uncertain significance ★ ⚠ same condition
MPEG1 p.Asn315= Uncertain significance ★ same condition
MPEG1 p.Gln227Ter Uncertain significance ★ same condition
MPEG1 p.Gly379Val Uncertain significance ★ ⚠ same condition
MPEG1 p.Gly530Glu 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/mpeg1-p-pro405thr (accessed [today's date]).

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