Is PITRM1 p.Leu145Val (c.433C>G) pathogenic?

PITRM1 p.Leu145Val (c.433C>G) is classified Benign in PITRM1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0811); Common (popmax 8.15%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about PITRM1 p.Leu145Val (c.433C>G)?

AlphaMissense predicts likely benign (score 0.0811) — an in-silico prediction, not a clinical call.

PITRM1 p.Leu145Val

Q: How common is PITRM1 p.Leu145Val (c.433C>G) in the general population?

PITRM1 p.Leu145Val (c.433C>G) is common (popmax 8.15%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.433C>G · rs9423502 · VCV1592796

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0811 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.15%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0811	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -5.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.23	acceptor gain, 14 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.62	GERP -3.6, phastCons 0.17
Regional constraint	o/e 1.12	unconstrained · MANE · 35 kb · p 2.6e-05 · regional, not allelic
Overall
CADD	13.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.15% Admixed American · 4,876/59,836 alleles

Filtering AF 7.96% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.88%

Overall 3.94% 62,657/1,591,452 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	8.15%	12
African / African-American	7.47%	13
Amishnot grpmax-eligible	5.15%	19
South Asian	4.81%	21
Middle Eastern	4.4%	23
Remaining individualsnot grpmax-eligible	4.27%	23
Finnishnot grpmax-eligible	4.13%	24
European (non-Finnish)	3.48%	29
Ashkenazi Jewishnot grpmax-eligible	3.4%	29
East Asian	2.18%	46

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.Leu145Val
Coding: c.433C>G
MANE Select: NM_014889
dbSNP: rs9423502
Type: single nucleotide variant
Location: chr10:3165513 (GRCh38)
Gene constraint: LOEUF 0.997 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 145: a disulfide bond; a UniProt-annotated variant site (in); a β-strand

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

Similar variants

PREP p.Ala145Thr Uncertain significance ★ ⚠ same residue
PITRM1 p.Leu145= Likely benign ★ 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-leu145val (accessed [today's date]).

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