Is MTRFR p.Arg99Ser (c.297A>T) pathogenic?

MTRFR p.Arg99Ser (c.297A>T) is classified Uncertain significance in MTRFR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-15). AlphaMissense: likely pathogenic (0.9815); Very rare (popmax 0.00167%, amr); Associated with Spastic paraplegia.

What condition is associated with MTRFR p.Arg99Ser (c.297A>T)?

MTRFR p.Arg99Ser (c.297A>T) is associated with Spastic paraplegia, combined oxidative phosphorylation defect type 7 (ClinVar).

How common is MTRFR p.Arg99Ser (c.297A>T) in the general population?

MTRFR p.Arg99Ser (c.297A>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MTRFR p.Arg99Ser (c.297A>T)?

AlphaMissense predicts likely pathogenic (score 0.9815) — an in-silico prediction, not a clinical call.

MTRFR p.Arg99Ser

c.297A>T · rs1459276555 · VCV998425

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9815 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.9815	likely pathogenic · top 2% in MTRFR
REVEL	0.563	indeterminate
SaProt	LLR -9.49	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP -0.96, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,353 bp · p 0.89 · regional, not allelic
Overall
CADD	23.7	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 0.00167% Admixed American · 1/59,982 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,612,382 alleles · very rare exomes 2/1,460,146 · genomes 1/152,236 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,982
European (non-Finnish)	0.00017%	589,282

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: MTRFR
Protein: p.Arg99Ser
Coding: c.297A>T
MANE Select: NM_152269
dbSNP: rs1459276555
Type: single nucleotide variant
Location: chr12:123256827 (GRCh38)
Gene constraint: LOEUF 1.224 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.56 · 1 PDB
Residue 99: a UniProt-annotated variant site (in coxpd7; decreased cytochrome c oxidase activity in fibroblasts; severe assembly defects in mitochondrial complexes i, iv and v with a milder defect in the assembly of complex iii; no effect on mitochondrial transcripts, rrnas and trnas levels); the 'ggq domain' region; a β-strand

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

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined oxidative phosphorylation defect type 7

Similar variants

MTRFR p.Arg99Lys Uncertain significance ★ ⚠ same residue
MTRFR p.Arg132Ter Pathogenic ★★ same condition
MTRFR p.Arg15Ter Pathogenic/Likely pathogenic ★★ same condition
MTRFR c.*439C>T Uncertain significance ★★ same condition
MTRFR p.Ala145Thr Uncertain significance ★★ ⚠ same condition
MTRFR p.Ala19Val Uncertain significance ★★ ⚠ same condition
MTRFR p.Arg109Trp Uncertain significance ★★ ⚠ same condition
MTRFR p.Arg24Gln 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/mtrfr-p-arg99ser (accessed [today's date]).

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