Is MIA3 p.Pro581Ser (c.1741C>T) pathogenic?

MIA3 p.Pro581Ser (c.1741C>T) is classified Uncertain significance in MIA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-03). AlphaMissense: likely benign (0.0786); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with MIA3 p.Pro581Ser (c.1741C>T)?

MIA3 p.Pro581Ser (c.1741C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MIA3 p.Pro581Ser (c.1741C>T) in the general population?

MIA3 p.Pro581Ser (c.1741C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about MIA3 p.Pro581Ser (c.1741C>T)?

AlphaMissense predicts likely benign (score 0.0786) — an in-silico prediction, not a clinical call.

MIA3 p.Pro581Ser

c.1741C>T · rs1662257358 · VCV2322317

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0786 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0786	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -5.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.48	GERP -3
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.3 · regional, not allelic
Overall
CADD	1.728	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 0.00133% African / African-American · 1/75,016 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,870 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,016
European (non-Finnish)	0.000169%	590,012

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: MIA3
Protein: p.Pro581Ser
Coding: c.1741C>T
MANE Select: NM_198551
dbSNP: rs1662257358
Type: single nucleotide variant
Location: chr1:222628961 (GRCh38)
Gene constraint: LOEUF 0.551 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.49 · 4 PDB
Residue 581: the 'disordered' region

Full MIA3 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

MIA3 p.Arg1809His Uncertain significance ★★ ⚠ same condition
MIA3 p.Thr791Arg Uncertain significance ★★ ⚠ same condition
MIA3 p.Thr910Ala Uncertain significance ★★ ⚠ same condition
MIA3 p.Val648Ala Uncertain significance ★★ ⚠ same condition
MIA3 p.Ala1054Thr Uncertain significance ★ ⚠ same condition
MIA3 p.Ala1133Ser Uncertain significance ★ ⚠ same condition
MIA3 p.Ala1133Thr Uncertain significance ★ ⚠ same condition
MIA3 p.Ala1145Thr 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/mia3-p-pro581ser (accessed [today's date]).

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