Is AIFM1 p.Pro335= (c.1005C>T) pathogenic?

AIFM1 p.Pro335= (c.1005C>T) is classified Likely benign in AIFM1 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-02-18). Very rare (popmax 0.00702%, afr); Associated with Charcot-Marie-Tooth Neuropathy X.

What condition is associated with AIFM1 p.Pro335= (c.1005C>T)?

AIFM1 p.Pro335= (c.1005C>T) is associated with Charcot-Marie-Tooth Neuropathy X, combined oxidative phosphorylation deficiency (ClinVar).

How common is AIFM1 p.Pro335= (c.1005C>T) in the general population?

AIFM1 p.Pro335= (c.1005C>T) is very rare (popmax 0.00702%, afr) (gnomAD).

AIFM1 p.Pro335=

c.1005C>T · rs371944474 · VCV2929649

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00702%, afr)

Conditions

Charcot-Marie-Tooth Neuropathy X

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 -0.56	GERP -3.5
Overall
CADD	2.791	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00702% African / African-American · 4/56,969 alleles

Filtering AF 0.00234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0014%

Overall 0.00198% 24/1,209,499 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00702%	14,242
Remaining individualsnot grpmax-eligible	0.0021%	47,593
European (non-Finnish)	0.00201%	49,732
South Asian	0.00176%	56,770

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.Pro335=
Coding: c.1005C>T
MANE Select: NM_004208
dbSNP: rs371944474
Type: single nucleotide variant
Location: chrX:130137148 (GRCh38)
Structure: AlphaFold pLDDT 85.97 · 26 PDB
Residue 335: a β-strand; the 'fad-dependent oxidoreductase' region

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

Disease context

Charcot-Marie-Tooth Neuropathy X — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined oxidative phosphorylation deficiency

Similar variants

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
AIFM1 p.Arg151Gln 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-pro335 (accessed [today's date]).

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