Is PHIP p.Trp855Ter (c.2564G>A) pathogenic?

PHIP p.Trp855Ter (c.2564G>A) is classified Likely pathogenic in PHIP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-14). Very rare (popmax 8.5e-05%, nfe); Associated with PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome.

How common is PHIP p.Trp855Ter (c.2564G>A) in the general population?

PHIP p.Trp855Ter (c.2564G>A) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

PHIP p.Trp855Ter

Q: What condition is associated with PHIP p.Trp855Ter (c.2564G>A)?

PHIP p.Trp855Ter (c.2564G>A) is associated with PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome (ClinVar).

Q: How is PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.2564G>A · rs2127718655 · VCV1324892

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Conditions

PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 23 of 40
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.99, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.5e-05% European (non-Finnish) · 1/1,176,620 alleles

Overall 6.23e-05% 1/1,606,286 alleles · very rare exomes 1/1,454,268 · genomes 0/152,018 · 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: PHIP
Protein: p.Trp855Ter
Coding: c.2564G>A
MANE Select: NM_017934
dbSNP: rs2127718655
Type: single nucleotide variant
Location: chr6:78983091 (GRCh38)
Gene constraint: LOEUF 0.246 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.57 · 146 PDB
Residue 855: the 'disordered' region; a UniProt-annotated variant site (in chujans)

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

Disease context

For PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Antenatal, Infancy, Neonatal

Similar variants

PHIP p.Arg110Cys Pathogenic/Likely pathogenic ★★ same condition
PHIP p.Arg178Ter Pathogenic/Likely pathogenic ★★ same condition
PHIP p.Arg255Ter Pathogenic/Likely pathogenic ★★ same condition
PHIP p.Arg396Ter Pathogenic/Likely pathogenic ★★ same condition
PHIP p.Arg503Ter Pathogenic/Likely pathogenic ★★ same condition
PHIP p.Arg721Ter Pathogenic/Likely pathogenic ★★ same condition
PHIP p.Asn507Ser Likely pathogenic ★★ ⚠ same condition
PHIP p.Gln274Ter Pathogenic ★★ 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-trp855ter (accessed [today's date]).

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