Is PITRM1 p.Arg183Trp (c.547C>T) pathogenic?

PITRM1 p.Arg183Trp (c.547C>T) is classified Uncertain significance in PITRM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-18). AlphaMissense: likely pathogenic (0.7556); Very rare (popmax 0.00454%, eas).

How common is PITRM1 p.Arg183Trp (c.547C>T) in the general population?

PITRM1 p.Arg183Trp (c.547C>T) is very rare (popmax 0.00454%, eas) (gnomAD).

What do computational predictors say about PITRM1 p.Arg183Trp (c.547C>T)?

AlphaMissense predicts likely pathogenic (score 0.7556) — an in-silico prediction, not a clinical call.

PITRM1 p.Arg183Trp

c.547C>T · rs576962834 · VCV2509120

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7556 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00454%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7556	likely pathogenic
REVEL	0.669	pathogenic-leaning
SaProt	LLR -14.19	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP -1.6, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 35 kb · p 2.6e-05 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00454% East Asian · 2/44,068 alleles

Filtering AF 0.00077% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000611%

Overall 0.00113% 18/1,591,144 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00454%	22,034
Admixed American	0.00178%	56,290
European (non-Finnish)	0.00128%	77,933

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.Arg183Trp
Coding: c.547C>T
MANE Select: NM_014889
dbSNP: rs576962834
Type: single nucleotide variant
Location: chr10:3165321 (GRCh38)
Gene constraint: LOEUF 0.997 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 183: a disulfide bond; a UniProt-annotated variant site (in scar30; decreased function in degradation of amyloid-beta protein 40; decreased metalloendopeptidase activity towards different substrates including an amyloid-beta peptide derivative; decreased protein levels in patient tissues; no effect on mitochondrial localization); a β-strand

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

Similar variants

PITRM1 p.Arg183Gln Uncertain significance ★ ⚠ same residue
PITRM1 p.Arg183Gly Uncertain significance ★ ⚠ same residue
PITRM1 p.Thr931Met Pathogenic/Likely pathogenic ★★ same type
PITRM1 p.Ala1003Thr Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala559Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala887Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala942Val Uncertain significance ★★ ⚠ same type
PITRM1 p.Ala965Thr 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-arg183trp (accessed [today's date]).

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