Is MRPS22 p.Phe331fs (c.992_993del) pathogenic?

MRPS22 p.Phe331fs (c.992993del) is classified Likely pathogenic in MRPS22 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-06). Very rare (popmax 0.00267%, afr); Associated with hypotonia with lactic acidemia and hyperammonemia.

What condition is associated with MRPS22 p.Phe331fs (c.992_993del)?

MRPS22 p.Phe331fs (c.992_993del) is associated with hypotonia with lactic acidemia and hyperammonemia (ClinVar).

How common is MRPS22 p.Phe331fs (c.992_993del) in the general population?

MRPS22 p.Phe331fs (c.992_993del) is very rare (popmax 0.00267%, afr) (gnomAD).

MRPS22 p.Phe331fs

Q: How is Hypotonia with lactic acidemia and hyperammonemia inherited?

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

c.992_993del · rs771036052 · VCV1806198

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

hypotonia with lactic acidemia and hyperammonemia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (8 of 8) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.086	GERP -2.4, phastCons 0.92
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,792 alleles

Filtering AF 0.00181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.00199% 32/1,610,624 alleles · very rare exomes 29/1,458,548 · genomes 3/152,076 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,396
European (non-Finnish)	0.00255%	39,255

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: MRPS22
Protein: p.Phe331fs
Coding: c.992_993del
MANE Select: NM_020191
dbSNP: rs771036052
Type: Deletion
Location: chr3:139356922 (GRCh38)
Gene constraint: LOEUF 0.927 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.51 · 86 PDB
Residue 331: an α-helix

Full MRPS22 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypotonia with lactic acidemia and hyperammonemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hypotonia with lactic acidemia and hyperammonemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal

Similar variants

MRPS22 p.Ala317fs Pathogenic ★ same condition
MRPS22 c.878+1G>T Pathogenic ★★ same condition
MRPS22 p.Arg170His Pathogenic/Likely pathogenic ★★ same condition
MRPS22 p.Asp292fs Pathogenic/Likely pathogenic ★★ same condition
MRPS22 p.Arg182Cys Uncertain significance ★★ ⚠ same condition
MRPS22 p.Arg263Cys Uncertain significance ★★ ⚠ same condition
MRPS22 p.Ile253Thr Uncertain significance ★★ ⚠ same condition
MRPS22 p.Lys244= 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/mrps22-p-phe331fs (accessed [today's date]).

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