Is PHYH p.Tyr46Phe (c.137A>T) pathogenic?

PHYH p.Tyr46Phe (c.137A>T) is classified Uncertain significance in PHYH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.1126); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PHYH p.Tyr46Phe (c.137A>T)?

PHYH p.Tyr46Phe (c.137A>T) is associated with Inborn genetic diseases (ClinVar).

How common is PHYH p.Tyr46Phe (c.137A>T) in the general population?

PHYH p.Tyr46Phe (c.137A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHYH p.Tyr46Phe (c.137A>T)?

AlphaMissense predicts likely benign (score 0.1126) — an in-silico prediction, not a clinical call.

PHYH p.Tyr46Phe

c.137A>T · VCV4136198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1126 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1126	likely benign
REVEL	0.431	indeterminate
SaProt	LLR -5.85	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 0.62, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 22 kb · p 0.67 · regional, not allelic
Overall
CADD	19.96	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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: PHYH
Protein: p.Tyr46Phe
Coding: c.137A>T
MANE Select: NM_006214
Type: single nucleotide variant
Location: chr10:13295604 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.33 · 1 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHYH p.Ala192Ser Uncertain significance ★★ ⚠ same condition
PHYH p.Ala244Gly Uncertain significance ★★ ⚠ same condition
PHYH p.Ala283Thr Uncertain significance ★★ same condition
PHYH p.Arg245Trp Uncertain significance ★★ ⚠ same condition
PHYH p.Arg80Cys Uncertain significance ★★ ⚠ same condition
PHYH p.Asp77Asn Uncertain significance ★★ ⚠ same condition
PHYH p.Gln42Arg Uncertain significance ★★ ⚠ same condition
PHYH p.Glu241Gly Uncertain significance ★★ ⚠ 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/phyh-p-tyr46phe (accessed [today's date]).

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