Is PTH p.Phe65Val (c.193T>G) pathogenic?

PTH p.Phe65Val (c.193T>G) is classified Uncertain significance in PTH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely benign (0.2827); Very rare (popmax 8.47e-05%, nfe).

How common is PTH p.Phe65Val (c.193T>G) in the general population?

PTH p.Phe65Val (c.193T>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PTH p.Phe65Val (c.193T>G)?

AlphaMissense predicts likely benign (score 0.2827) — an in-silico prediction, not a clinical call.

PTH p.Phe65Val

c.193T>G · VCV4147193

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2827 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2827	likely benign
REVEL	0.525	indeterminate
SaProt	LLR -4.72	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 6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 447 bp · p 0.43 · regional, not allelic
Overall
CADD	24.3	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,022 alleles

Overall 6.2e-05% 1/1,614,152 alleles · very rare exomes 1/1,461,872 · genomes 0/152,280 · 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: PTH
Protein: p.Phe65Val
Coding: c.193T>G
MANE Select: NM_000315
Type: single nucleotide variant
Location: chr11:13492560 (GRCh38)
Gene constraint: LOEUF 1.32 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 72.93 · 26 PDB
Residue 65: an α-helix; the 'important for receptor binding' region

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

Similar variants

PTH p.Arg56Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
PTH c.-33C>T Uncertain significance ★★ same type
PTH p.Ala77Asp Uncertain significance ★★ ⚠ same type
PTH c.86+9T>G Benign ★★ same type
PTH c.87-50G>A Benign ★★ same type
PTH c.-5-10G>A Benign/Likely benign ★★ same type
PTH c.-5-98G>A Benign ★★ same type
PTH c.*319A>G Benign ★★ 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/pth-p-phe65val (accessed [today's date]).

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