Is PDCD6IP p.Ala726Val (c.2177C>T) pathogenic?

PDCD6IP p.Ala726Val (c.2177C>T) is classified Uncertain significance in PDCD6IP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-16). AlphaMissense: likely benign (0.1191); Ultra-rare (popmax 0.0293%, afr).

How common is PDCD6IP p.Ala726Val (c.2177C>T) in the general population?

PDCD6IP p.Ala726Val (c.2177C>T) is ultra-rare (popmax 0.0293%, afr) (gnomAD).

What do computational predictors say about PDCD6IP p.Ala726Val (c.2177C>T)?

AlphaMissense predicts likely benign (score 0.1191) — an in-silico prediction, not a clinical call.

PDCD6IP p.Ala726Val

c.2177C>T · rs149493155 · VCV2228740

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1191 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0293%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1191	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -6.72	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 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,508 bp · p 0.82 · regional, not allelic
Overall
CADD	24.6	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 0.0293% African / African-American · 22/75,040 alleles

Filtering AF 0.0198% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00372% 60/1,614,040 alleles · ultra-rare exomes 46/1,461,724 · genomes 14/152,316 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0293%	3,411
Admixed American	0.00666%	15,004
Remaining individualsnot grpmax-eligible	0.0064%	15,625
European (non-Finnish)	0.00237%	42,140
East Asian	0.00223%	44,878
South Asian	0.0011%	91,076

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.Ala726Val
Coding: c.2177C>T
MANE Select: NM_013374
dbSNP: rs149493155
Type: single nucleotide variant
Location: chr3:33864062 (GRCh38)
Gene constraint: LOEUF 0.583 · pLI 0.19 (gnomAD)
Structure: AlphaFold pLDDT 84.16 · 19 PDB
Residue 726: 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 residue
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
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-ala726val (accessed [today's date]).

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