Is NDUFA2 p.Arg34Ser (c.102G>C) pathogenic?

NDUFA2 p.Arg34Ser (c.102G>C) is classified Uncertain significance in NDUFA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-05). AlphaMissense: likely pathogenic (0.9804); Very rare (popmax 0.00267%, afr).

How common is NDUFA2 p.Arg34Ser (c.102G>C) in the general population?

NDUFA2 p.Arg34Ser (c.102G>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about NDUFA2 p.Arg34Ser (c.102G>C)?

AlphaMissense predicts likely pathogenic (score 0.9804) — an in-silico prediction, not a clinical call.

NDUFA2 p.Arg34Ser

c.102G>C · VCV3690984

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9804 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9804	likely pathogenic · top 1% in NDUFA2
REVEL	0.575	indeterminate
SaProt	LLR -15.28	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.39	acceptor loss · deltas
Pangolin	Δ0.32	loss · gain 0.22 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1	GERP 0.79, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 1,993 bp · p 0.1 · regional, not allelic
Overall
CADD	26.7	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 0.00267% African / African-American · 2/74,802 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,610,284 alleles · very rare exomes 1/1,458,108 · genomes 1/152,176 · joint denominator

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: NDUFA2
Protein: p.Arg34Ser
Coding: c.102G>C
MANE Select: NM_002488
Type: single nucleotide variant
Location: chr5:140647362 (GRCh38)
Gene constraint: LOEUF 1.343 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.11 · 8 PDB
Residue 34: an α-helix

Full NDUFA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NDUFA2 p.Lys64Arg Uncertain significance ★★ ⚠ same type
NDUFA2 p.Phe82Cys Uncertain significance ★★ ⚠ same type
NDUFA2 p.Ser27Trp Uncertain significance ★★ same type
NDUFA2 p.Ser96Asn Uncertain significance ★★ ⚠ same type
NDUFA2 p.Val94Ile Uncertain significance ★★ ⚠ same type
NDUFA2 c.208+18G>A Benign/Likely benign ★★ same type
NDUFA2 c.209-28T>C Likely benign ★★ same type
NDUFA2 c.-136A>G Benign ★★ same type

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/ndufa2-p-arg34ser (accessed [today's date]).

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