Is PHIP p.Cys28Arg (c.82T>C) pathogenic?

PHIP p.Cys28Arg (c.82T>C) is classified Uncertain significance in PHIP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-14). AlphaMissense: likely pathogenic (0.9979); No allele count reported in gnomAD v4.1 (AN 1,564,440); Associated with PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome.

How common is PHIP p.Cys28Arg (c.82T>C) in the general population?

PHIP p.Cys28Arg (c.82T>C) is no allele count reported in gnomAD v4.1 (AN 1,564,440) (gnomAD).

What do computational predictors say about PHIP p.Cys28Arg (c.82T>C)?

AlphaMissense predicts likely pathogenic (score 0.9979) — an in-silico prediction, not a clinical call.

PHIP p.Cys28Arg

Q: What condition is associated with PHIP p.Cys28Arg (c.82T>C)?

PHIP p.Cys28Arg (c.82T>C) 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.82T>C · VCV3367608

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9979 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,564,440)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.9979	likely pathogenic · top 7% in PHIP
REVEL	0.275	benign-leaning
SaProt	LLR -16.12	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.3, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 572 bp · p 0.14 · regional, not allelic
Overall
CADD	24.3	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

No allele count reported in gnomAD v4.1 (AN 1,564,440). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PHIP
Protein: p.Cys28Arg
Coding: c.82T>C
MANE Select: NM_017934
Type: single nucleotide variant
Location: chr6:79077872 (GRCh38)
Gene constraint: LOEUF 0.246 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.57 · 146 PDB

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-cys28arg (accessed [today's date]).

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