Is PTEN p.Tyr46His (c.136T>C) pathogenic?

PTEN p.Tyr46His (c.136T>C) is classified Likely pathogenic in PTEN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-01). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1; Associated with PTEN-related disorder.

What condition is associated with PTEN p.Tyr46His (c.136T>C)?

PTEN p.Tyr46His (c.136T>C) is associated with PTEN-related disorder (ClinVar).

How common is PTEN p.Tyr46His (c.136T>C) in the general population?

PTEN p.Tyr46His (c.136T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PTEN p.Tyr46His (c.136T>C)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

PTEN p.Tyr46His

c.136T>C · rs1064793325 · VCV1701143

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PTEN-related disorder

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic ✓ concordant with ClinVar · top 8% in PTEN
REVEL	0.965	strongly pathogenic-leaning
SaProt	LLR -13.12	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 7.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.27	constrained · MANE · 69 kb · p 6.5e-17 · regional, not allelic
Overall
CADD	31.0	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

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: PTEN
Protein: p.Tyr46His
Coding: c.136T>C
MANE Select: NM_000314
dbSNP: rs1064793325
Type: single nucleotide variant
Location: chr10:87894081 (GRCh38)
Gene constraint: LOEUF 0.685 · pLI 0.05 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.76 · 12 PDB
Residue 46: a β-strand; the phosphatase tensin-type domain

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

Disease context

PTEN-related disorder

Similar variants

PTEN p.Tyr46Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
PTEN p.Tyr46Asn Likely pathogenic ★ same residue
PTEN p.Tyr46Ter Pathogenic ★ same residue
PTEN p.Tyr46Asp Conflicting classifications of pathogenicity ★ ⚠ same residue
PTEN c.164+2T>A Pathogenic/Likely pathogenic ★★ same condition
PTEN c.209+1G>C Pathogenic ★★ same condition
PTEN c.210-1G>C Pathogenic/Likely pathogenic ★★ same condition
PTEN c.634+1G>C Pathogenic ★★ same condition

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/pten-p-tyr46his (accessed [today's date]).

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