Is PDCD6IP p.Pro749= (c.2247T>C) pathogenic?

PDCD6IP p.Pro749= (c.2247T>C) is classified Benign in PDCD6IP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-29). Common (popmax 5.22%, afr) — too common for a highly-penetrant pathogenic allele.

PDCD6IP p.Pro749=

Q: How common is PDCD6IP p.Pro749= (c.2247T>C) in the general population?

PDCD6IP p.Pro749= (c.2247T>C) is common (popmax 5.22%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2247T>C · rs74450908 · VCV709749

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 5.22%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.28	GERP 1.9, phastCons 0.001
Overall
CADD	11.92	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.22% African / African-American · 3,620/69,318 alleles

Filtering AF 5.08% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.02%

Overall 0.267% 4,086/1,532,506 alleles · common exomes 1,782/1,380,208 · genomes 2,304/152,298 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.22%	19
Remaining individualsnot grpmax-eligible	0.357%	280
Admixed American	0.343%	292
Middle Eastern	0.274%	365
South Asian	0.0129%	7,724
European (non-Finnish)	0.00765%	13,067

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.Pro749=
Coding: c.2247T>C
MANE Select: NM_013374
dbSNP: rs74450908
Type: single nucleotide variant
Location: chr3:33865245 (GRCh38)
Gene constraint: LOEUF 0.583 · pLI 0.19 (gnomAD)
Structure: AlphaFold pLDDT 84.16 · 19 PDB
Residue 749: 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.Ala726= Likely benign ★★ same type
PDCD6IP p.Gly429Ser Benign ★★ ⚠ same type
PDCD6IP p.Gly778Ala 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
PDCD6IP p.Ala726Val Uncertain significance ★ ⚠ same type
PDCD6IP p.Ala736Gly Uncertain significance ★ ⚠ 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-pro749 (accessed [today's date]).

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