Is PHIP p.Glu727Val (c.2180A>T) pathogenic?

PHIP p.Glu727Val (c.2180A>T) is classified Uncertain significance in PHIP (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-25). AlphaMissense: likely pathogenic (0.6942); Very rare (popmax 8.48e-05%, nfe).

How common is PHIP p.Glu727Val (c.2180A>T) in the general population?

PHIP p.Glu727Val (c.2180A>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PHIP p.Glu727Val (c.2180A>T)?

AlphaMissense predicts likely pathogenic (score 0.6942) — an in-silico prediction, not a clinical call.

PHIP p.Glu727Val

c.2180A>T · rs1337758901 · VCV2430343

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6942	likely pathogenic
REVEL	0.505	indeterminate
SaProt	LLR -1.72	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 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 11 kb · p 7.6e-13 · regional, not allelic
Overall
CADD	27.4	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 8.48e-05% European (non-Finnish) · 1/1,179,844 alleles

Overall 6.2e-05% 1/1,613,820 alleles · very rare exomes 1/1,461,646 · genomes 0/152,174 · 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.Glu727Val
Coding: c.2180A>T
MANE Select: NM_017934
dbSNP: rs1337758901
Type: single nucleotide variant
Location: chr6:78997435 (GRCh38)
Gene constraint: LOEUF 0.246 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.57 · 146 PDB
Residue 727: a UniProt-annotated variant site (in chujans)

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

Similar variants

PHIP p.Arg110Cys Pathogenic/Likely pathogenic ★★ same type
PHIP p.Arg178Ter Pathogenic/Likely pathogenic ★★ same type
PHIP p.Arg193Ter Pathogenic ★★ same type
PHIP p.Arg255Ter Pathogenic/Likely pathogenic ★★ same type
PHIP p.Arg396Ter Pathogenic/Likely pathogenic ★★ same type
PHIP p.Arg503Ter Pathogenic/Likely pathogenic ★★ same type
PHIP p.Arg721Ter Pathogenic/Likely pathogenic ★★ same type
PHIP p.Asn507Ser Likely pathogenic ★★ ⚠ same type

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-glu727val (accessed [today's date]).

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