Is TG p.Ala327Val (c.980C>T) pathogenic?

TG p.Ala327Val (c.980C>T) is classified Uncertain significance in TG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-01). AlphaMissense: likely benign (0.109); Ultra-rare (popmax 0.016%, afr); Associated with Inborn genetic diseases.

What condition is associated with TG p.Ala327Val (c.980C>T)?

TG p.Ala327Val (c.980C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TG p.Ala327Val (c.980C>T) in the general population?

TG p.Ala327Val (c.980C>T) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about TG p.Ala327Val (c.980C>T)?

AlphaMissense predicts likely benign (score 0.109) — an in-silico prediction, not a clinical call.

TG p.Ala327Val

c.980C>T · VCV3806362

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.109 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.109	likely benign
REVEL	0.206	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 -0.22	GERP 1.1
Regional constraint	o/e 1.04	unconstrained · MANE · 268 kb · p 0.022 · regional, not allelic
Overall
CADD	20.8	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 0.016% African / African-American · 12/74,926 alleles

Filtering AF 0.00921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00304% 49/1,614,084 alleles · ultra-rare exomes 37/1,461,888 · genomes 12/152,196 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,244
European (non-Finnish)	0.00288%	34,707
Admixed American	0.00167%	60,014
Remaining individualsnot grpmax-eligible	0.0016%	62,490
South Asian	0.0011%	91,088

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.Ala327Val
Coding: c.980C>T
MANE Select: NM_003235
Type: single nucleotide variant
Location: chr8:132882904 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Residue 327: a β-strand; the thyroglobulin type-1 4 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TG p.Ala327Thr Uncertain significance ★ ⚠ same residue
TG p.Ala327= Conflicting classifications of pathogenicity ★ same residue
TG p.Ala1033Val Uncertain significance ★★ ⚠ same condition
TG p.Ala1419Glu Uncertain significance ★★ same condition
TG p.Ala1419Val Uncertain significance ★★ ⚠ same condition
TG p.Ala1583Val Uncertain significance ★★ ⚠ same condition
TG p.Ala1631Ser Uncertain significance ★★ ⚠ same condition
TG p.Ala402Gly 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/tg-p-ala327val (accessed [today's date]).

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