Is PHIP p.Arg752Gly (c.2254A>G) pathogenic?

PHIP p.Arg752Gly (c.2254A>G) is classified Likely benign in PHIP (ClinVar, Single submitter, 2 submitters; last evaluated 2024-07-24). AlphaMissense: ambiguous (0.374); Ultra-rare (popmax 0.016%, afr).

How common is PHIP p.Arg752Gly (c.2254A>G) in the general population?

PHIP p.Arg752Gly (c.2254A>G) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about PHIP p.Arg752Gly (c.2254A>G)?

AlphaMissense predicts ambiguous (score 0.374) — an in-silico prediction, not a clinical call.

PHIP p.Arg752Gly

c.2254A>G · rs754990621 · VCV2874736

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.374 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.374	ambiguous
REVEL	0.208	benign-leaning
SaProt	LLR -9.39	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 5,581 bp · p 0.29 · regional, not allelic
Overall
CADD	22.6	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 0.016% African / African-American · 12/74,856 alleles

Filtering AF 0.00922% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.000931% 15/1,611,822 alleles · ultra-rare exomes 8/1,459,632 · genomes 7/152,190 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,238
Admixed American	0.00334%	29,957
European (non-Finnish)	8.49e-05%	1,178,425

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.Arg752Gly
Coding: c.2254A>G
MANE Select: NM_017934
dbSNP: rs754990621
Type: single nucleotide variant
Location: chr6:78990933 (GRCh38)
Gene constraint: LOEUF 0.246 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 66.57 · 146 PDB
Residue 752: the 'disordered' region; 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.Arg752= Benign/Likely benign ★★ same residue
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

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-arg752gly (accessed [today's date]).

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