Is SHMT2 p.Arg41fs (c.121_122del) pathogenic?

SHMT2 p.Arg41fs (c.121122del) is classified Uncertain significance in SHMT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-12). Ultra-rare (popmax 0.0165%, mid).

How common is SHMT2 p.Arg41fs (c.121_122del) in the general population?

SHMT2 p.Arg41fs (c.121_122del) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

SHMT2 p.Arg41fs

c.121_122del · rs761732423 · VCV3063886

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 2 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.53	GERP -4.5, phastCons 0.46
Overall
CADD	23.8	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 0.0165% Middle Eastern · 1/6,064 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00149% 24/1,613,982 alleles · ultra-rare exomes 20/1,461,862 · genomes 4/152,120 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,064
East Asian	0.00223%	44,888
South Asian	0.0022%	45,541
European (non-Finnish)	0.00161%	62,107
Finnishnot grpmax-eligible	0.00156%	64,020

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: SHMT2
Protein: p.Arg41fs
Coding: c.121_122del
MANE Select: NM_005412
dbSNP: rs761732423
Type: Deletion
Location: chr12:57230890 (GRCh38)
Gene constraint: LOEUF 0.794 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.24 · 33 PDB
Residue 41: the 'disordered' region

Full SHMT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/shmt2-p-arg41fs (accessed [today's date]).

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