Is PHIP p.Pro726= (c.2178C>T) pathogenic?

PHIP p.Pro726= (c.2178C>T) is classified Likely benign in PHIP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-22). Very rare (popmax 0.0022%, sas); Associated with PHIP-related disorder.

What condition is associated with PHIP p.Pro726= (c.2178C>T)?

PHIP p.Pro726= (c.2178C>T) is associated with PHIP-related disorder (ClinVar).

How common is PHIP p.Pro726= (c.2178C>T) in the general population?

PHIP p.Pro726= (c.2178C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

PHIP p.Pro726=

c.2178C>T · VCV3355137

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

PHIP-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP -4, phastCons 1
Overall
CADD	11.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,028 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000434% 7/1,613,592 alleles · very rare exomes 7/1,461,502 · genomes 0/152,090 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,514
European (non-Finnish)	0.000424%	235,951

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: PHIP
Protein: p.Pro726=
Coding: c.2178C>T
MANE Select: NM_017934
Type: single nucleotide variant
Location: chr6:78997437 (GRCh38)
Gene constraint: LOEUF 0.246 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.57 · 146 PDB
Residue 726: a UniProt-annotated variant site (in chujans)

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

Disease context

PHIP-related disorder

Similar variants

PHIP p.Pro726Ser Likely pathogenic ★ ⚠ same residue
PHIP p.Val771Ile Uncertain significance ★★ ⚠ same condition
PHIP c.1096-2A>C Likely pathogenic ★ same condition
PHIP c.822+1G>A Likely pathogenic ★ same condition
PHIP p.Glu55Ter Likely pathogenic ★ same condition
PHIP p.Glu755Ter Likely pathogenic ★ same condition
PHIP p.Tyr602Ter Likely pathogenic ★ same condition
PHIP p.Ile812Val 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/phip-p-pro726 (accessed [today's date]).

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