Is PHIP p.Pro474Gln (c.1421C>A) pathogenic?

PHIP p.Pro474Gln (c.1421C>A) is classified Uncertain significance in PHIP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-17). AlphaMissense: likely pathogenic (0.6052); Very rare (popmax 8.5e-05%, nfe); Associated with PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome.

How common is PHIP p.Pro474Gln (c.1421C>A) in the general population?

PHIP p.Pro474Gln (c.1421C>A) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about PHIP p.Pro474Gln (c.1421C>A)?

AlphaMissense predicts likely pathogenic (score 0.6052) — an in-silico prediction, not a clinical call.

PHIP p.Pro474Gln

Q: What condition is associated with PHIP p.Pro474Gln (c.1421C>A)?

PHIP p.Pro474Gln (c.1421C>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.1421C>A · VCV3376427

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6052 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.6052	likely pathogenic
REVEL	0.34	indeterminate
SaProt	LLR -8.71	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 22 kb · p 1e-18 · regional, not allelic
Overall
CADD	25.9	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 8.5e-05% European (non-Finnish) · 1/1,176,892 alleles

Overall 6.21e-05% 1/1,610,084 alleles · very rare exomes 1/1,458,382 · genomes 0/151,702 · 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.Pro474Gln
Coding: c.1421C>A
MANE Select: NM_017934
Type: single nucleotide variant
Location: chr6:79015185 (GRCh38)
Gene constraint: LOEUF 0.246 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.57 · 146 PDB
Residue 474: 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.Pro474Ser Uncertain significance ★ ⚠ same residue
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

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-pro474gln (accessed [today's date]).

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