Is PDIA5 p.Ala59Val (c.176C>T) pathogenic?

PDIA5 p.Ala59Val (c.176C>T) is classified Uncertain significance in PDIA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-02). AlphaMissense: likely benign (0.1004); Very rare (popmax 0.00017%, nfe).

How common is PDIA5 p.Ala59Val (c.176C>T) in the general population?

PDIA5 p.Ala59Val (c.176C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about PDIA5 p.Ala59Val (c.176C>T)?

AlphaMissense predicts likely benign (score 0.1004) — an in-silico prediction, not a clinical call.

PDIA5 p.Ala59Val

c.176C>T · rs546101783 · VCV3210921

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1004 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1004	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -7.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	acceptor loss, 6 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 95 kb · p 0.49 · regional, not allelic
Overall
CADD	23.0	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 0.00017% European (non-Finnish) · 2/1,178,918 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,460,510 alleles · very rare

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: PDIA5
Protein: p.Ala59Val
Coding: c.176C>T
MANE Select: NM_006810
dbSNP: rs546101783
Type: single nucleotide variant
Location: chr3:123092361 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.49 · 1 PDB
Residue 59: an α-helix

Full PDIA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PDIA5 p.Ala133Val Uncertain significance ★ ⚠ same type
PDIA5 p.Ala150Val Uncertain significance ★ ⚠ same type
PDIA5 p.Ala179Val Uncertain significance ★ ⚠ same type
PDIA5 p.Ala334Pro Uncertain significance ★ ⚠ same type
PDIA5 p.Ala342Gly Uncertain significance ★ ⚠ same type
PDIA5 p.Ala365Thr Uncertain significance ★ ⚠ same type
PDIA5 p.Ala384Asp Uncertain significance ★ ⚠ same type
PDIA5 p.Ala469Gly 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/pdia5-p-ala59val (accessed [today's date]).

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