Is TBX2 p.Pro329His (c.986C>A) pathogenic?

TBX2 p.Pro329His (c.986C>A) is classified Likely benign in TBX2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-07-01). AlphaMissense: likely benign (0.1179); Rare (popmax 0.352%, nfe).

How common is TBX2 p.Pro329His (c.986C>A) in the general population?

TBX2 p.Pro329His (c.986C>A) is rare (popmax 0.352%, nfe) (gnomAD).

What do computational predictors say about TBX2 p.Pro329His (c.986C>A)?

AlphaMissense predicts likely benign (score 0.1179) — an in-silico prediction, not a clinical call.

TBX2 p.Pro329His

c.986C>A · rs182290035 · VCV775111

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1179 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.352%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1179	likely benign
REVEL	0.253	benign-leaning
SaProt	LLR -8.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 0.68, phastCons 0.54
Regional constraint	o/e 1.04	unconstrained · MANE · 4,018 bp · p 0.3 · regional, not allelic
Overall
CADD	22.1	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

Grpmax group 0.352% European (non-Finnish) · 4,075/1,156,888 alleles

Filtering AF 0.343% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.34%

Overall 0.28% 4,393/1,567,464 alleles · rare exomes 4,102/1,415,104 · genomes 291/152,360 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	5.15%	19
European (non-Finnish)grpmax	0.352%	284
Remaining individualsnot grpmax-eligible	0.182%	551
Admixed American	0.0723%	1,384
Middle Eastern	0.0668%	1,497
African / African-American	0.0598%	1,673
Ashkenazi Jewishnot grpmax-eligible	0.0555%	1,803
Finnishnot grpmax-eligible	0.041%	2,441
South Asian	0.0395%	2,534

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TBX2
Protein: p.Pro329His
Coding: c.986C>A
MANE Select: NM_005994
dbSNP: rs182290035
Type: single nucleotide variant
Location: chr17:61404704 (GRCh38)
Gene constraint: LOEUF 0.832 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 58.13
Residue 329: the 'disordered' region

Full TBX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TBX2 p.Arg20Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
TBX2 p.Ala374Thr Uncertain significance ★★ ⚠ same type
TBX2 p.Arg185His Uncertain significance ★★ ⚠ same type
TBX2 p.Arg616Trp Uncertain significance ★★ ⚠ same type
TBX2 p.Gly536Arg Uncertain significance ★★ same type
TBX2 p.Leu304Val Uncertain significance ★★ ⚠ same type
TBX2 p.Lys148Gln Uncertain significance ★★ ⚠ same type
TBX2 p.Pro39Gln 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/tbx2-p-pro329his (accessed [today's date]).

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