Is TAC3 p.Arg80Ser (c.238C>A) pathogenic?

TAC3 p.Arg80Ser (c.238C>A) is classified Likely pathogenic in TAC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2014-11-01). AlphaMissense: likely pathogenic (0.896); Absent from gnomAD v4.1; Associated with hypogonadotropic hypogonadism 7 with or without anosmia.

What condition is associated with TAC3 p.Arg80Ser (c.238C>A)?

TAC3 p.Arg80Ser (c.238C>A) is associated with hypogonadotropic hypogonadism 7 with or without anosmia (ClinVar).

How common is TAC3 p.Arg80Ser (c.238C>A) in the general population?

TAC3 p.Arg80Ser (c.238C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TAC3 p.Arg80Ser (c.238C>A)?

AlphaMissense predicts likely pathogenic (score 0.896) — an in-silico prediction, not a clinical call.

TAC3 p.Arg80Ser

c.238C>A · rs727505372 · VCV180155

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.896 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hypogonadotropic hypogonadism 7 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.896	likely pathogenic ✓ concordant with ClinVar · top 3% in TAC3
REVEL	0.543	indeterminate
SaProt	LLR -11.02	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 3,415 bp · p 0.1 · regional, not allelic
Overall
CADD	24.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TAC3
Protein: p.Arg80Ser
Coding: c.238C>A
MANE Select: NM_013251
dbSNP: rs727505372
Type: single nucleotide variant
Location: chr12:57013359 (GRCh38)
Gene constraint: LOEUF 0.927 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 65.34 · 2 PDB
Residue 80: a UniProt-annotated variant site (in hh10; phenotype consistent with normosmic idiopathic hypogonadotropic hypogonadism; the patient also carries a mutation in hs6st1)

Full TAC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypogonadotropic hypogonadism 7 with or without anosmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TAC3 p.Arg80Cys Uncertain significance ★ ⚠ same residue
TAC3 p.Gln45Arg Uncertain significance ★★ ⚠ same type
TAC3 c.114+87G>T Benign ★★ same type
TAC3 c.292+162A>G Benign ★★ same type
TAC3 c.*19C>T Benign ★★ same type
TAC3 p.Ser99Pro Benign ★★ same type
TAC3 c.238+1G>C Likely pathogenic ★ same type
TAC3 c.209-1G>C 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/tac3-p-arg80ser (accessed [today's date]).

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