Is TOR1A p.Phe269Ser (c.806T>C) pathogenic?

TOR1A p.Phe269Ser (c.806T>C) is classified Uncertain significance in TOR1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-25). AlphaMissense: likely pathogenic (0.9938); Absent from gnomAD v4.1.

How common is TOR1A p.Phe269Ser (c.806T>C) in the general population?

TOR1A p.Phe269Ser (c.806T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TOR1A p.Phe269Ser (c.806T>C)?

AlphaMissense predicts likely pathogenic (score 0.9938) — an in-silico prediction, not a clinical call.

TOR1A p.Phe269Ser

c.806T>C · VCV3341042

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9938 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9938	likely pathogenic · top 5% in TOR1A
REVEL	0.845	moderately pathogenic-leaning
SaProt	LLR -12.60	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 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 10 kb · p 0.042 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TOR1A
Protein: p.Phe269Ser
Coding: c.806T>C
MANE Select: NM_000113
Type: single nucleotide variant
Location: chr9:129814165 (GRCh38)
Gene constraint: LOEUF 0.84 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.82 · 3 PDB
Residue 269: the 'interaction with klc1' region; a β-strand

Full TOR1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TOR1A p.Arg282Ter Likely pathogenic ★★ same type
TOR1A p.Arg288Ter Pathogenic/Likely pathogenic ★★ same type
TOR1A c.-4G>C Uncertain significance ★★ same type
TOR1A p.Ala239Thr Uncertain significance ★★ ⚠ same type
TOR1A p.Ala239Val Uncertain significance ★★ ⚠ same type
TOR1A p.Arg213Gly Uncertain significance ★★ ⚠ same type
TOR1A p.Arg260Trp Uncertain significance ★★ ⚠ same type
TOR1A p.Asp331Asn 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/tor1a-p-phe269ser (accessed [today's date]).

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