Is PDCD6IP p.Pro748Arg (c.2243C>G) pathogenic?

PDCD6IP p.Pro748Arg (c.2243C>G) is classified Uncertain significance in PDCD6IP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely benign (0.3377); Ultra-rare (popmax 0.0592%, amr).

How common is PDCD6IP p.Pro748Arg (c.2243C>G) in the general population?

PDCD6IP p.Pro748Arg (c.2243C>G) is ultra-rare (popmax 0.0592%, amr) (gnomAD).

What do computational predictors say about PDCD6IP p.Pro748Arg (c.2243C>G)?

AlphaMissense predicts likely benign (score 0.3377) — an in-silico prediction, not a clinical call.

PDCD6IP p.Pro748Arg

c.2243C>G · VCV4566212

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3377 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0592%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3377	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -10.08	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,508 bp · p 0.82 · regional, not allelic
Overall
CADD	20.9	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 0.0592% Admixed American · 35/59,074 alleles

Filtering AF 0.0438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0384%

Overall 0.00239% 36/1,503,148 alleles · ultra-rare exomes 23/1,350,958 · genomes 13/152,190 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0592%	1,688
Remaining individualsnot grpmax-eligible	0.0017%	58,708

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: PDCD6IP
Protein: p.Pro748Arg
Coding: c.2243C>G
MANE Select: NM_013374
Type: single nucleotide variant
Location: chr3:33864128 (GRCh38)
Gene constraint: LOEUF 0.583 · pLI 0.19 (gnomAD)
Structure: AlphaFold pLDDT 84.16 · 19 PDB
Residue 748: the 'interaction with eiav p9' region; the 'interaction with sdcbp' region; the 'self-association' region; the 'disordered' region

Full PDCD6IP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDCD6IP p.Pro748Leu Uncertain significance ★ ⚠ same residue
PDCD6IP p.Ala726= Likely benign ★★ same type
PDCD6IP p.Gly429Ser Benign ★★ ⚠ same type
PDCD6IP p.Gly778Ala Benign ★★ same type
PDCD6IP p.Pro749= Benign ★★ same type
PDCD6IP p.Thr789= Benign ★★ same type
PDCD6IP p.Ala657Val Uncertain significance ★ ⚠ same type
PDCD6IP p.Ala719Thr Conflicting classifications of pathogenicity ★ ⚠ 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/pdcd6ip-p-pro748arg (accessed [today's date]).

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