Is PITRM1 p.Ser669Phe (c.2006C>T) pathogenic?

PITRM1 p.Ser669Phe (c.2006C>T) is classified Uncertain significance in PITRM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-12). AlphaMissense: likely benign (0.1296); Ultra-rare (popmax 0.033%, mid); Associated with spinocerebellar ataxia, autosomal recessive 30.

What condition is associated with PITRM1 p.Ser669Phe (c.2006C>T)?

PITRM1 p.Ser669Phe (c.2006C>T) is associated with spinocerebellar ataxia, autosomal recessive 30 (ClinVar).

How common is PITRM1 p.Ser669Phe (c.2006C>T) in the general population?

PITRM1 p.Ser669Phe (c.2006C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about PITRM1 p.Ser669Phe (c.2006C>T)?

AlphaMissense predicts likely benign (score 0.1296) — an in-silico prediction, not a clinical call.

PITRM1 p.Ser669Phe

c.2006C>T · VCV3896943

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1296 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

spinocerebellar ataxia, autosomal recessive 30

Computational evidence

Protein change
AlphaMissense	0.1296	likely benign
REVEL	0.505	indeterminate
SaProt	LLR -11.82	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 0.68, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 35 kb · p 2.6e-05 · regional, not allelic
Overall
CADD	25.2	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 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000342% 5/1,461,450 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.00017%	589,831

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.Ser669Phe
Coding: c.2006C>T
MANE Select: NM_014889
Type: single nucleotide variant
Location: chr10:3148050 (GRCh38)
Gene constraint: LOEUF 0.997 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.44 · 8 PDB
Residue 669: a β-strand

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

Disease context

spinocerebellar ataxia, autosomal recessive 30 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PITRM1 p.Thr931Met Pathogenic/Likely pathogenic ★★ same condition
PITRM1 p.Arg545Gln Uncertain significance ★★ ⚠ same condition
PITRM1 p.Arg183Gln Uncertain significance ★ ⚠ same condition
PITRM1 p.Tyr923Asp Conflicting classifications of pathogenicity ★ ⚠ same condition
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

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-ser669phe (accessed [today's date]).

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