Is AIFM1 p.Pro545Ser (c.1633C>T) pathogenic?

AIFM1 p.Pro545Ser (c.1633C>T) is classified Benign in AIFM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-10). AlphaMissense: likely benign (0.0607); Ultra-rare (popmax 0.0175%, afr); Associated with Charcot-Marie-Tooth Neuropathy X.

What condition is associated with AIFM1 p.Pro545Ser (c.1633C>T)?

AIFM1 p.Pro545Ser (c.1633C>T) is associated with Charcot-Marie-Tooth Neuropathy X, combined oxidative phosphorylation deficiency (ClinVar).

How common is AIFM1 p.Pro545Ser (c.1633C>T) in the general population?

AIFM1 p.Pro545Ser (c.1633C>T) is ultra-rare (popmax 0.0175%, afr) (gnomAD).

What do computational predictors say about AIFM1 p.Pro545Ser (c.1633C>T)?

AlphaMissense predicts likely benign (score 0.0607) — an in-silico prediction, not a clinical call.

AIFM1 p.Pro545Ser

c.1633C>T · rs139322490 · VCV859916

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0607 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0175%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Charcot-Marie-Tooth Neuropathy X

Computational evidence

Protein change
AlphaMissense	0.0607	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -3.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.38	acceptor gain · deltas
Pangolin	Δ0.30	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.044	GERP -3.2, phastCons 0.063
Regional constraint	o/e 1.15	unconstrained · MANE · 1,693 bp · p 0.3 · regional, not allelic
Overall
CADD	10.49	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0175% African / African-American · 10/57,207 alleles

Filtering AF 0.00941% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00721%

Overall 0.00116% 14/1,210,110 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0175%	5,721
Remaining individualsnot grpmax-eligible	0.0021%	47,623
European (non-Finnish)	0.000335%	298,430

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.Pro545Ser
Coding: c.1633C>T
MANE Select: NM_004208
dbSNP: rs139322490
Type: single nucleotide variant
Location: chrX:130130107 (GRCh38)
Structure: AlphaFold pLDDT 85.97 · 26 PDB
Residue 545: the 'disordered' 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-pro545ser (accessed [today's date]).

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