Is AIFM1 p.Pro28= (c.84G>A) pathogenic?

AIFM1 p.Pro28= (c.84G>A) is classified Likely benign in AIFM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). Ultra-rare (popmax 0.0112%, amr); Associated with combined oxidative phosphorylation deficiency.

What condition is associated with AIFM1 p.Pro28= (c.84G>A)?

AIFM1 p.Pro28= (c.84G>A) is associated with combined oxidative phosphorylation deficiency (ClinVar).

How common is AIFM1 p.Pro28= (c.84G>A) in the general population?

AIFM1 p.Pro28= (c.84G>A) is ultra-rare (popmax 0.0112%, amr) (gnomAD).

AIFM1 p.Pro28=

c.84G>A · rs762259913 · VCV703417

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, amr)

Conditions

combined oxidative phosphorylation deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1	GERP -3.5, phastCons 0.002
Overall
CADD	11.31	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0112% Admixed American · 5/44,642 alleles

Filtering AF 0.00436% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00277%

Overall 0.000417% 5/1,198,162 alleles · ultra-rare exomes 5/1,084,187 · genomes 0/113,975 · joint denominator

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: AIFM1
Protein: p.Pro28=
Coding: c.84G>A
MANE Select: NM_004208
dbSNP: rs762259913
Type: single nucleotide variant
Location: chrX:130165573 (GRCh38)
Structure: AlphaFold pLDDT 85.97 · 26 PDB

Full AIFM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined oxidative phosphorylation deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AIFM1 p.Pro28Gln Uncertain significance ★★ ⚠ same residue
AIFM1 p.Arg422Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
AIFM1 p.Arg422Trp Pathogenic/Likely pathogenic ★★ same condition
AIFM1 p.Met340Thr Pathogenic/Likely pathogenic ★★ same condition
AIFM1 c.1448+5T>C Uncertain significance ★★ same condition
AIFM1 c.782-3C>T Uncertain significance ★★ same condition
AIFM1 p.Ala117Val Uncertain significance ★★ ⚠ same condition
AIFM1 p.Ala80Thr 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/aifm1-p-pro28 (accessed [today's date]).

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