Is PITRM1 p.Val415Ala (c.1244T>C) pathogenic?

PITRM1 p.Val415Ala (c.1244T>C) is classified Uncertain significance in PITRM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.0884); Very rare (popmax 8.67e-05%, nfe).

How common is PITRM1 p.Val415Ala (c.1244T>C) in the general population?

PITRM1 p.Val415Ala (c.1244T>C) is very rare (popmax 8.67e-05%, nfe) (gnomAD).

What do computational predictors say about PITRM1 p.Val415Ala (c.1244T>C)?

AlphaMissense predicts likely benign (score 0.0884) — an in-silico prediction, not a clinical call.

PITRM1 p.Val415Ala

c.1244T>C · VCV4137277

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0884 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.67e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0884	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -10.57	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	GERP 0.51, phastCons 0.99
Regional constraint	o/e 1.12	unconstrained · MANE · 35 kb · p 2.6e-05 · regional, not allelic
Overall
CADD	22.4	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 8.67e-05% European (non-Finnish) · 1/1,153,294 alleles

Overall 6.31e-05% 1/1,585,226 alleles · very rare exomes 1/1,432,878 · genomes 0/152,348 · joint denominator

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.Val415Ala
Coding: c.1244T>C
MANE Select: NM_014889
Type: single nucleotide variant
Location: chr10:3158046 (GRCh38)
Gene constraint: LOEUF 0.997 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 415: an α-helix

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

Similar variants

PREP p.Glu415Gly 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
PITRM1 p.Arg32Trp 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-val415ala (accessed [today's date]).

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