Is RRM2B p.Val69= (c.207C>T) pathogenic?

RRM2B p.Val69= (c.207C>T) is classified Benign in RRM2B (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-02). Low-frequency (popmax 3.85%, nfe); Associated with mitochondrial DNA depletion syndrome 8a.

What condition is associated with RRM2B p.Val69= (c.207C>T)?

RRM2B p.Val69= (c.207C>T) is associated with mitochondrial DNA depletion syndrome 8a, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 (ClinVar).

How common is RRM2B p.Val69= (c.207C>T) in the general population?

RRM2B p.Val69= (c.207C>T) is low-frequency (popmax 3.85%, nfe) (gnomAD).

RRM2B p.Val69=

Q: How is Mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy inherited?

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

c.207C>T · rs28999710 · VCV138929

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.85%, nfe)

Conditions

mitochondrial DNA depletion syndrome 8a

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.76 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.4	GERP -3.8, phastCons 1
Overall
CADD	11.78	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.85% European (non-Finnish) · 44,460/1,153,940 alleles

Filtering AF 3.82% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.81%

Overall 3.38% 53,556/1,585,052 alleles · low-frequency exomes 49,521/1,432,900 · genomes 4,035/152,152 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	5.9%	17
European (non-Finnish)grpmax	3.85%	26
Remaining individualsnot grpmax-eligible	2.93%	34
Amishnot grpmax-eligible	2.08%	48
Admixed American	1.98%	51
South Asian	1.55%	65
Ashkenazi Jewishnot grpmax-eligible	1.31%	76
Middle Eastern	1.08%	92
African / African-American	0.64%	156
East Asian	0.0112%	8,930

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: RRM2B
Protein: p.Val69=
Coding: c.207C>T
MANE Select: NM_015713
dbSNP: rs28999710
Type: single nucleotide variant
Location: chr8:102226032 (GRCh38)
Gene constraint: LOEUF 0.688 · pLI 0.27 (gnomAD)
Structure: AlphaFold pLDDT 85.73 · 3 PDB

Full RRM2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

mitochondrial DNA depletion syndrome 8a — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5

For Mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

RRM2B p.Val69Ile Uncertain significance ★ ⚠ same residue
RRM2B c.322-2A>G Pathogenic ★★ same condition
RRM2B c.455+1G>A Likely pathogenic ★★ same condition
RRM2B p.Arg110Cys Likely pathogenic ★★ same condition
RRM2B p.Arg174Ter Pathogenic/Likely pathogenic ★★ same condition
RRM2B p.Arg327Ter Pathogenic ★★ same condition
RRM2B p.Arg41Trp Pathogenic/Likely pathogenic ★★ same condition
RRM2B p.Gly229Val Pathogenic/Likely pathogenic ★★ 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/rrm2b-p-val69 (accessed [today's date]).

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