Is MRPL3 p.Ser288Pro (c.862T>C) pathogenic?

MRPL3 p.Ser288Pro (c.862T>C) is classified Uncertain significance in MRPL3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-20). AlphaMissense: likely benign (0.2135); Rare (popmax 0.201%, mid); Associated with combined oxidative phosphorylation defect type 9.

What condition is associated with MRPL3 p.Ser288Pro (c.862T>C)?

MRPL3 p.Ser288Pro (c.862T>C) is associated with combined oxidative phosphorylation defect type 9 (ClinVar).

How common is MRPL3 p.Ser288Pro (c.862T>C) in the general population?

MRPL3 p.Ser288Pro (c.862T>C) is rare (popmax 0.201%, mid) (gnomAD).

What do computational predictors say about MRPL3 p.Ser288Pro (c.862T>C)?

AlphaMissense predicts likely benign (score 0.2135) — an in-silico prediction, not a clinical call.

MRPL3 p.Ser288Pro

Q: How is Combined oxidative phosphorylation defect type 9 inherited?

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

c.862T>C · rs143788120 · VCV1027733

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2135 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.201%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

combined oxidative phosphorylation defect type 9

Computational evidence

Protein change
AlphaMissense	0.2135	likely benign
REVEL	0.412	indeterminate
SaProt	LLR -7.78	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 40 kb · p 0.3 · regional, not allelic
Overall
CADD	27.6	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 0.201% Middle Eastern · 12/5,958 alleles

Filtering AF 0.116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0911%

Overall 0.0341% 543/1,594,540 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.201%	496
Remaining individualsnot grpmax-eligible	0.0454%	2,202
European (non-Finnish)	0.0397%	2,521
Admixed American	0.032%	3,128
Finnishnot grpmax-eligible	0.0126%	7,957
African / African-American	0.0109%	9,216
South Asian	0.0046%	21,733

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: MRPL3
Protein: p.Ser288Pro
Coding: c.862T>C
MANE Select: NM_007208
dbSNP: rs143788120
Type: single nucleotide variant
Location: chr3:131468123 (GRCh38)
Gene constraint: LOEUF 1.403 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.20 · 92 PDB

Full MRPL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

combined oxidative phosphorylation defect type 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined oxidative phosphorylation defect type 9 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

MRPL3 c.93-2A>C Likely pathogenic ★ same condition
MRPL3 p.Pro317Arg Likely pathogenic ★ same condition
MRPL3 p.Cys127Arg Uncertain significance ★ ⚠ same condition
MRPL3 p.Tyr265His Uncertain significance ★ ⚠ same condition
MRPL3 p.Val118Met Uncertain significance ★ ⚠ same condition
MRPL3 p.Ala185Val Uncertain significance ★★ ⚠ same type
MRPL3 p.Arg199His Uncertain significance ★★ ⚠ same type
MRPL3 p.Arg275Lys Uncertain significance ★★ ⚠ 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/mrpl3-p-ser288pro (accessed [today's date]).

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