Is JPH3 p.Arg656Trp (c.1966C>T) pathogenic?

JPH3 p.Arg656Trp (c.1966C>T) is classified Likely benign in JPH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). AlphaMissense: likely benign (0.1537); Rare (popmax 0.136%, sas).

How common is JPH3 p.Arg656Trp (c.1966C>T) in the general population?

JPH3 p.Arg656Trp (c.1966C>T) is rare (popmax 0.136%, sas) (gnomAD).

What do computational predictors say about JPH3 p.Arg656Trp (c.1966C>T)?

AlphaMissense predicts likely benign (score 0.1537) — an in-silico prediction, not a clinical call.

JPH3 p.Arg656Trp

c.1966C>T · rs201403180 · VCV710778

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1537 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.136%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1537	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -8.20	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 0.89	GERP -2.4, phastCons 0.99
Regional constraint	o/e 1.16	unconstrained · MANE · 93 kb · p 6.9e-07 · regional, not allelic
Overall
CADD	23.0	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

Grpmax group 0.136% South Asian · 119/87,466 alleles

Filtering AF 0.116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.109%

Overall 0.067% 1,063/1,586,642 alleles · rare exomes 1,006/1,434,334 · genomes 57/152,308 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.136%	735
European (non-Finnish)	0.0765%	1,308
Remaining individualsnot grpmax-eligible	0.0571%	1,751
Middle Eastern	0.0334%	2,994
African / African-American	0.00946%	10,575
Ashkenazi Jewishnot grpmax-eligible	0.00695%	14,398
Admixed American	0.00536%	18,665
Finnishnot grpmax-eligible	0.00328%	30,443

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.Arg656Trp
Coding: c.1966C>T
MANE Select: NM_020655
dbSNP: rs201403180
Type: single nucleotide variant
Location: chr16:87690326 (GRCh38)
Gene constraint: LOEUF 0.36 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.52

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-arg656trp (accessed [today's date]).

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