Is MTRFR p.Phe64Ser (c.191T>C) pathogenic?

MTRFR p.Phe64Ser (c.191T>C) is classified Uncertain significance in MTRFR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-13). AlphaMissense: likely pathogenic (0.8504); Very rare (popmax 0.00534%, afr); Associated with Spastic paraplegia.

What condition is associated with MTRFR p.Phe64Ser (c.191T>C)?

MTRFR p.Phe64Ser (c.191T>C) is associated with Spastic paraplegia, combined oxidative phosphorylation defect type 7 (ClinVar).

How common is MTRFR p.Phe64Ser (c.191T>C) in the general population?

MTRFR p.Phe64Ser (c.191T>C) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about MTRFR p.Phe64Ser (c.191T>C)?

AlphaMissense predicts likely pathogenic (score 0.8504) — an in-silico prediction, not a clinical call.

MTRFR p.Phe64Ser

c.191T>C · rs771507731 · VCV2184097

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8504 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.8504	likely pathogenic
REVEL	0.54	indeterminate
SaProt	LLR -15.06	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.54, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,353 bp · p 0.89 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,904 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000372% 6/1,614,028 alleles · very rare exomes 1/1,461,880 · genomes 5/152,148 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,726
East Asian	0.00223%	44,896
European (non-Finnish)	8.47e-05%	1,180,040

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.Phe64Ser
Coding: c.191T>C
MANE Select: NM_152269
dbSNP: rs771507731
Type: single nucleotide variant
Location: chr12:123253865 (GRCh38)
Gene constraint: LOEUF 1.224 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.56 · 1 PDB
Residue 64: a β-strand; the 'ggq domain' region

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.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
MTRFR p.Arg24Leu 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-phe64ser (accessed [today's date]).

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