Is PHIP p.Pro642Leu (c.1925C>T) pathogenic?

PHIP p.Pro642Leu (c.1925C>T) is classified Uncertain significance in PHIP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-18). AlphaMissense: likely benign (0.2825); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PHIP p.Pro642Leu (c.1925C>T)?

PHIP p.Pro642Leu (c.1925C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PHIP p.Pro642Leu (c.1925C>T) in the general population?

PHIP p.Pro642Leu (c.1925C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about PHIP p.Pro642Leu (c.1925C>T)?

AlphaMissense predicts likely benign (score 0.2825) — an in-silico prediction, not a clinical call.

PHIP p.Pro642Leu

c.1925C>T · rs2482046704 · VCV2549048

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2825 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2825	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -4.95	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 11 kb · p 7.6e-13 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,410 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,346 alleles · very rare exomes 3/1,461,150 · genomes 0/152,196 · 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.Pro642Leu
Coding: c.1925C>T
MANE Select: NM_017934
dbSNP: rs2482046704
Type: single nucleotide variant
Location: chr6:78998346 (GRCh38)
Gene constraint: LOEUF 0.246 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.57 · 146 PDB
Residue 642: a UniProt-annotated variant site (in chujans)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHIP p.Arg160Gly Uncertain significance ★★ ⚠ same condition
PHIP p.Arg346Gln Uncertain significance ★★ ⚠ same condition
PHIP p.Arg691Leu Uncertain significance ★★ ⚠ same condition
PHIP p.Arg799Ile Uncertain significance ★★ ⚠ same condition
PHIP p.Arg837Thr Uncertain significance ★★ ⚠ same condition
PHIP p.Asn795His Uncertain significance ★★ ⚠ same condition
PHIP p.Gln638Glu Uncertain significance ★★ ⚠ same condition
PHIP p.Gly412Ser 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-pro642leu (accessed [today's date]).

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