Is JPH3 p.Pro435= (c.1305G>A) pathogenic?

JPH3 p.Pro435= (c.1305G>A) is classified Likely benign in JPH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-12-29). Ultra-rare (popmax 0.0134%, eas).

How common is JPH3 p.Pro435= (c.1305G>A) in the general population?

JPH3 p.Pro435= (c.1305G>A) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

JPH3 p.Pro435=

c.1305G>A · rs755283278 · VCV722210

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.91	GERP -2.4
Overall
CADD	3.434	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,854 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00403% 65/1,611,950 alleles · ultra-rare exomes 55/1,459,778 · genomes 10/152,172 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0255%	3,923
East Asiangrpmax	0.0134%	7,476
South Asian	0.0055%	18,184
Remaining individualsnot grpmax-eligible	0.0032%	31,208
European (non-Finnish)	0.00288%	34,694
African / African-American	0.00267%	37,437

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: JPH3
Protein: p.Pro435=
Coding: c.1305G>A
MANE Select: NM_020655
dbSNP: rs755283278
Type: single nucleotide variant
Location: chr16:87689665 (GRCh38)
Gene constraint: LOEUF 0.36 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.52
Residue 435: the 'disordered' region

Full JPH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

JPH3 p.Arg319Trp Uncertain significance ★★ ⚠ same type
JPH3 p.Leu266Val Uncertain significance ★★ ⚠ same type
JPH3 p.Thr175Met Uncertain significance ★★ ⚠ same type
JPH3 c.2167-9C>G Benign/Likely benign ★★ same type
JPH3 p.Ala271= Benign/Likely benign ★★ same type
JPH3 p.Ala366= Likely benign ★★ same type
JPH3 p.Ala384= Likely benign ★★ same type
JPH3 p.Ala523= Benign/Likely 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/jph3-p-pro435 (accessed [today's date]).

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