Is MTRR p.His558fs (c.1672dup) pathogenic?

MTRR p.His558fs (c.1672dup) is classified Likely pathogenic in MTRR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-30). No gnomAD frequency available for this variant; Associated with neural tube defects, folate-sensitive.

What condition is associated with MTRR p.His558fs (c.1672dup)?

MTRR p.His558fs (c.1672dup) is associated with neural tube defects, folate-sensitive (ClinVar).

How common is MTRR p.His558fs (c.1672dup) in the general population?

MTRR p.His558fs (c.1672dup) is no gnomAD frequency available for this variant (gnomAD).

MTRR p.His558fs

c.1672dup · rs2476220505 · VCV2676861

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

neural tube defects, folate-sensitive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.2	GERP -3

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MTRR
Protein: p.His558fs
Coding: c.1672dup
MANE Select: NM_002454
dbSNP: rs2476220505
Type: Duplication
Location: chr5:7895847 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.79 · 2 PDB
Residue 558: an α-helix

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

Disease context

neural tube defects, folate-sensitive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MTRR p.Leu235fs Pathogenic/Likely pathogenic ★★ same condition
MTRR p.Lys109fs Likely pathogenic ★★ same condition
MTRR p.Asn504fs Likely pathogenic ★ same condition
MTRR p.His558= Likely benign ★ same residue
MTRR c.1057+1G>A Likely pathogenic ★★ same condition
MTRR c.1146+1G>A Likely pathogenic ★★ same condition
MTRR c.1554_1557+3del Pathogenic/Likely pathogenic ★★ same condition
MTRR c.1676+2T>C 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/mtrr-p-his558fs (accessed [today's date]).

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