Is VARS2 p.Ser424= (c.1272C>T) pathogenic?

VARS2 p.Ser424= (c.1272C>T) is classified Benign in VARS2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Common (popmax 56.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with combined oxidative phosphorylation defect type 20.

What condition is associated with VARS2 p.Ser424= (c.1272C>T)?

VARS2 p.Ser424= (c.1272C>T) is associated with combined oxidative phosphorylation defect type 20 (ClinVar).

VARS2 p.Ser424=

Q: How common is VARS2 p.Ser424= (c.1272C>T) in the general population?

VARS2 p.Ser424= (c.1272C>T) is common (popmax 56.7%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Combined oxidative phosphorylation defect type 20 inherited?

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

c.1272C>T · rs2285319 · VCV380152

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 56.7%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

combined oxidative phosphorylation defect type 20

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.1	GERP -2.7
Overall
CADD	4.533	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 56.7% East Asian · 25,239/44,502 alleles

Filtering AF 56.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 55.9%

Overall 21% 331,985/1,582,470 alleles · common exomes 295,312/1,430,418 · genomes 36,673/152,052 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	56.7%	2
South Asian	45.9%	2
Admixed American	42.6%	2
Amishnot grpmax-eligible	29.9%	3
Finnishnot grpmax-eligible	25.3%	4
Remaining individualsnot grpmax-eligible	24.6%	4
Middle Eastern	24.5%	4
Ashkenazi Jewishnot grpmax-eligible	24.2%	4
African / African-American	23.5%	4
European (non-Finnish)	16%	6

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: VARS2
Protein: p.Ser424=
Coding: c.1272C>T
MANE Select: NM_020442
dbSNP: rs2285319
Type: single nucleotide variant
Location: chr6:30920195 (GRCh38)
Structure: AlphaFold pLDDT 88.12

Full VARS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined oxidative phosphorylation defect type 20 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined oxidative phosphorylation defect type 20 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

VARS2 c.1480-2A>G Likely pathogenic ★★ same condition
VARS2 c.2467-2A>G Pathogenic/Likely pathogenic ★★ same condition
VARS2 p.Arg363Ter Pathogenic/Likely pathogenic ★★ same condition
VARS2 p.Glu486Ter Pathogenic/Likely pathogenic ★★ same condition
VARS2 p.Thr337Ile Pathogenic ★★ same condition
VARS2 p.Arg1002Gln Uncertain significance ★★ ⚠ same condition
VARS2 p.Arg168Cys Uncertain significance ★★ ⚠ same condition
VARS2 p.Arg168His 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/vars2-p-ser424 (accessed [today's date]).

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