Is TXNRD2 p.Ala59= (c.177C>T) pathogenic?

TXNRD2 p.Ala59= (c.177C>T) is classified Benign in TXNRD2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 86.3%, eas) — too common for a highly-penetrant pathogenic allele; Associated with glucocorticoid deficiency 5.

What condition is associated with TXNRD2 p.Ala59= (c.177C>T)?

TXNRD2 p.Ala59= (c.177C>T) is associated with glucocorticoid deficiency 5, dilated cardiomyopathy (ClinVar).

How is Familial glucocorticoid deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TXNRD2 p.Ala59=

Q: How common is TXNRD2 p.Ala59= (c.177C>T) in the general population?

TXNRD2 p.Ala59= (c.177C>T) is common (popmax 86.3%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.177C>T · rs5748470 · VCV263370

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 86.3%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

glucocorticoid deficiency 5

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 0.19	GERP -3.1, phastCons 0.38
Overall
CADD	3.165	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 86.3% East Asian · 35,343/40,944 alleles

Filtering AF 85.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 85.3%

Overall 52.3% 814,039/1,557,060 alleles · common exomes 736,329/1,405,424 · genomes 77,710/151,636 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	86.3%	1
Admixed American	66.2%	2
South Asian	62.1%	2
Finnishnot grpmax-eligible	59.3%	2
Ashkenazi Jewishnot grpmax-eligible	59.2%	2
Remaining individualsnot grpmax-eligible	54%	2
Amishnot grpmax-eligible	50.8%	2
Middle Eastern	50.4%	2
European (non-Finnish)	49.9%	2
African / African-American	40.4%	2

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: TXNRD2
Protein: p.Ala59=
Coding: c.177C>T
MANE Select: NM_006440
dbSNP: rs5748470
Type: single nucleotide variant
Location: chr22:19919595 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Residue 59: a binding site

Full TXNRD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

glucocorticoid deficiency 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy

For Familial glucocorticoid deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Ireland)

Similar variants

TXNRD2 p.Ala59Pro Uncertain significance ★★ same residue
TXNRD2 p.Ala59Thr Uncertain significance ★★ same residue
TXNRD2 c.104-1G>A Uncertain significance ★★ same condition
TXNRD2 c.104-3C>G Uncertain significance ★★ same condition
TXNRD2 c.1086+4C>T Uncertain significance ★★ same condition
TXNRD2 c.1087-2A>G Uncertain significance ★★ same condition
TXNRD2 c.1348-2A>G Uncertain significance ★★ same condition
TXNRD2 c.1348-9G>A Uncertain significance ★★ same condition

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/txnrd2-p-ala59 (accessed [today's date]).

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