Is MIA3 p.Pro899Ala (c.2695C>G) pathogenic?

MIA3 p.Pro899Ala (c.2695C>G) is classified Uncertain significance in MIA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-27). AlphaMissense: likely benign (0.0718); Rare (popmax 0.169%, afr); Associated with Inborn genetic diseases.

What condition is associated with MIA3 p.Pro899Ala (c.2695C>G)?

MIA3 p.Pro899Ala (c.2695C>G) is associated with Inborn genetic diseases (ClinVar).

How common is MIA3 p.Pro899Ala (c.2695C>G) in the general population?

MIA3 p.Pro899Ala (c.2695C>G) is rare (popmax 0.169%, afr) (gnomAD).

What do computational predictors say about MIA3 p.Pro899Ala (c.2695C>G)?

AlphaMissense predicts likely benign (score 0.0718) — an in-silico prediction, not a clinical call.

MIA3 p.Pro899Ala

c.2695C>G · rs374709745 · VCV3126056

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0718 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.169%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0718	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -5.94	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 1	GERP 0.89, phastCons 0.001
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.3 · regional, not allelic
Overall
CADD	4.606	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 0.169% African / African-American · 127/75,020 alleles

Filtering AF 0.145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.136%

Overall 0.00849% 137/1,614,058 alleles · rare exomes 49/1,461,792 · genomes 88/152,266 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.169%	591
Remaining individualsnot grpmax-eligible	0.008%	12,502
Admixed American	0.00666%	15,006
South Asian	0.0011%	91,078

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.Pro899Ala
Coding: c.2695C>G
MANE Select: NM_198551
dbSNP: rs374709745
Type: single nucleotide variant
Location: chr1:222629915 (GRCh38)
Gene constraint: LOEUF 0.551 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.49 · 4 PDB
Residue 899: 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

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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-pro899ala (accessed [today's date]).

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