Is PITRM1 p.Asp409fs (c.1227_1230del) pathogenic?

PITRM1 p.Asp409fs (c.12271230del) is classified Uncertain significance in PITRM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-22). Very rare (popmax 0.00446%, eas).

How common is PITRM1 p.Asp409fs (c.1227_1230del) in the general population?

PITRM1 p.Asp409fs (c.1227_1230del) is very rare (popmax 0.00446%, eas) (gnomAD).

PITRM1 p.Asp409fs

c.1227_1230del · VCV4906464

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

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 11 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.2	GERP 1.6, phastCons 1
Overall
CADD	21.6	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 0.00446% East Asian · 2/44,878 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000431%

Overall 0.00106% 17/1,605,022 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,439
South Asian	0.0022%	45,466
African / African-American	0.00134%	74,802
European (non-Finnish)	0.00102%	97,640

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: PITRM1
Protein: p.Asp409fs
Coding: c.1227_1230del
MANE Select: NM_014889
Type: Deletion
Location: chr10:3158060 (GRCh38)
Gene constraint: LOEUF 0.997 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 409: an α-helix

Full PITRM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PITRM1 p.Asp409Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
PITRM1 c.1622-15_1622-3del Benign/Likely benign ★★ same type
PITRM1 c.533+19_533+22del Benign/Likely benign ★★ same type
PITRM1 c.630+13_630+16del Likely benign ★★ same type
PITRM1 p.Lys808fs Likely pathogenic ★ same type
PITRM1 c.2337-2_2337-1del Uncertain significance ★ same type
PITRM1 p.Gln987fs Uncertain significance ★ same type
PITRM1 p.Ser958fs 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/pitrm1-p-asp409fs (accessed [today's date]).

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