Is PTH p.Val66Ile (c.196G>A) pathogenic?

PTH p.Val66Ile (c.196G>A) is classified Likely benign in PTH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-13). AlphaMissense: likely benign (0.0795); Ultra-rare (popmax 0.0145%, nfe).

How common is PTH p.Val66Ile (c.196G>A) in the general population?

PTH p.Val66Ile (c.196G>A) is ultra-rare (popmax 0.0145%, nfe) (gnomAD).

What do computational predictors say about PTH p.Val66Ile (c.196G>A)?

AlphaMissense predicts likely benign (score 0.0795) — an in-silico prediction, not a clinical call.

PTH p.Val66Ile

c.196G>A · rs200119869 · VCV2379132

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0795 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0145%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0795	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -6.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.41	GERP -3.4
Regional constraint	o/e 0.93	unconstrained · MANE · 447 bp · p 0.43 · regional, not allelic
Overall
CADD	0.969	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 0.0145% European (non-Finnish) · 171/1,180,036 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.012%

Overall 0.0108% 174/1,614,026 alleles · ultra-rare exomes 160/1,461,870 · genomes 14/152,156 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0145%	6,901
Remaining individualsnot grpmax-eligible	0.0032%	31,245
African / African-American	0.00133%	74,920

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.Val66Ile
Coding: c.196G>A
MANE Select: NM_000315
dbSNP: rs200119869
Type: single nucleotide variant
Location: chr11:13492557 (GRCh38)
Gene constraint: LOEUF 1.32 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 72.93 · 26 PDB
Residue 66: 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-val66ile (accessed [today's date]).

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