Is MTRFR p.Pro12Ser (c.34C>T) pathogenic?

MTRFR p.Pro12Ser (c.34C>T) is classified Uncertain significance in MTRFR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-20). AlphaMissense: likely benign (0.0748); Ultra-rare (popmax 0.0198%, sas); Associated with combined oxidative phosphorylation defect type 7.

What condition is associated with MTRFR p.Pro12Ser (c.34C>T)?

MTRFR p.Pro12Ser (c.34C>T) is associated with combined oxidative phosphorylation defect type 7 (ClinVar).

How common is MTRFR p.Pro12Ser (c.34C>T) in the general population?

MTRFR p.Pro12Ser (c.34C>T) is ultra-rare (popmax 0.0198%, sas) (gnomAD).

What do computational predictors say about MTRFR p.Pro12Ser (c.34C>T)?

AlphaMissense predicts likely benign (score 0.0748) — an in-silico prediction, not a clinical call.

MTRFR p.Pro12Ser

Q: How is Combined oxidative phosphorylation defect type 7 inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.34C>T · rs751310720 · VCV307494

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0748 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0198%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

combined oxidative phosphorylation defect type 7

Computational evidence

Protein change
AlphaMissense	0.0748	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -0.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.92 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.63	GERP -3.5
Regional constraint	o/e 0.99	unconstrained · MANE · 3,353 bp · p 0.89 · regional, not allelic
Overall
CADD	0.034	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0198% South Asian · 18/91,080 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00164% 24/1,461,894 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0198%	5,060
Remaining individualsnot grpmax-eligible	0.0032%	31,251
European (non-Finnish)	0.000339%	295,010

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.Pro12Ser
Coding: c.34C>T
MANE Select: NM_152269
dbSNP: rs751310720
Type: single nucleotide variant
Location: chr12:123253708 (GRCh38)
Gene constraint: LOEUF 1.224 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.56 · 1 PDB

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

Disease context

combined oxidative phosphorylation defect type 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined oxidative phosphorylation defect type 7 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

MTRFR p.Pro12fs Pathogenic ★ 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-pro12ser (accessed [today's date]).

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