Is AIFM1 p.Pro18= (c.54C>G) pathogenic?

AIFM1 p.Pro18= (c.54C>G) is classified Benign/Likely benign in AIFM1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-04-24). Rare (popmax 0.131%, afr); Associated with combined oxidative phosphorylation deficiency.

What condition is associated with AIFM1 p.Pro18= (c.54C>G)?

AIFM1 p.Pro18= (c.54C>G) is associated with combined oxidative phosphorylation deficiency (ClinVar).

How common is AIFM1 p.Pro18= (c.54C>G) in the general population?

AIFM1 p.Pro18= (c.54C>G) is rare (popmax 0.131%, afr) (gnomAD).

AIFM1 p.Pro18=

c.54C>G · rs140076585 · VCV512658

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.131%, afr)

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 2.3	GERP -0.34, phastCons 1
Overall
CADD	12.19	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.131% African / African-American · 75/57,312 alleles

Filtering AF 0.107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0982%

Overall 0.00773% 93/1,202,385 alleles · rare exomes 40/1,089,846 · genomes 53/112,539 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.131%	764
Remaining individualsnot grpmax-eligible	0.0106%	9,451
Admixed American	0.00885%	11,303
European (non-Finnish)	0.00101%	99,004

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.Pro18=
Coding: c.54C>G
MANE Select: NM_004208
dbSNP: rs140076585
Type: single nucleotide variant
Location: chrX:130165603 (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.Pro18Leu 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-pro18 (accessed [today's date]).

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