Is TG p.Ala397Asp (c.1190C>A) pathogenic?

TG p.Ala397Asp (c.1190C>A) is classified Uncertain significance in TG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-27). AlphaMissense: likely benign (0.0879); Very rare (popmax 0.0011%, nfe); Associated with congenital hypothyroidism.

What condition is associated with TG p.Ala397Asp (c.1190C>A)?

TG p.Ala397Asp (c.1190C>A) is associated with congenital hypothyroidism (ClinVar).

How common is TG p.Ala397Asp (c.1190C>A) in the general population?

TG p.Ala397Asp (c.1190C>A) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about TG p.Ala397Asp (c.1190C>A)?

AlphaMissense predicts likely benign (score 0.0879) — an in-silico prediction, not a clinical call.

TG p.Ala397Asp

c.1190C>A · VCV4683068

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0879 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

congenital hypothyroidism

Computational evidence

Protein change
AlphaMissense	0.0879	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.3	GERP -4.4
Regional constraint	o/e 1.04	unconstrained · MANE · 268 kb · p 0.022 · regional, not allelic
Overall
CADD	0.01	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,180,040 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000805% 13/1,614,220 alleles · very rare exomes 13/1,461,894 · genomes 0/152,326 · joint denominator

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: TG
Protein: p.Ala397Asp
Coding: c.1190C>A
MANE Select: NM_003235
Type: single nucleotide variant
Location: chr8:132886562 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)

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

Disease context

congenital hypothyroidism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TG p.Ala397= Likely benign ★ same residue
TG c.5686+1G>T Pathogenic ★★ same condition
TG p.Ala2234Asp Pathogenic/Likely pathogenic ★★ same condition
TG p.Arg1530Ter Pathogenic ★★ same condition
TG p.Arg159Ter Pathogenic/Likely pathogenic ★★ same condition
TG p.Arg296Ter Pathogenic ★★ same condition
TG p.Gln771Ter Pathogenic/Likely pathogenic ★★ same condition
TG p.Glu39Ter Pathogenic/Likely pathogenic ★★ 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/tg-p-ala397asp (accessed [today's date]).

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