Is TBCE p.Pro72Ser (c.214C>T) pathogenic?

TBCE p.Pro72Ser (c.214C>T) is classified Benign/Likely benign in TBCE (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-04-01). AlphaMissense: ambiguous (0.3534); Rare (popmax 0.335%, nfe); Associated with hypoparathyroidism-retardation-dysmorphism syndrome.

What condition is associated with TBCE p.Pro72Ser (c.214C>T)?

TBCE p.Pro72Ser (c.214C>T) is associated with hypoparathyroidism-retardation-dysmorphism syndrome (ClinVar).

How common is TBCE p.Pro72Ser (c.214C>T) in the general population?

TBCE p.Pro72Ser (c.214C>T) is rare (popmax 0.335%, nfe) (gnomAD).

What do computational predictors say about TBCE p.Pro72Ser (c.214C>T)?

AlphaMissense predicts ambiguous (score 0.3534) — an in-silico prediction, not a clinical call.

TBCE p.Pro72Ser

c.214C>T · rs62620041 · VCV286377

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

ambiguous

0.3534 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.335%, nfe)

Conditions

hypoparathyroidism-retardation-dysmorphism syndrome

Computational evidence

Protein change
AlphaMissense	0.3534	ambiguous
REVEL	0.305	indeterminate
SaProt	LLR -9.68	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 69 kb · p 0.95 · regional, not allelic
Overall
CADD	24.4	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 0.335% European (non-Finnish) · 3,952/1,179,966 alleles

Filtering AF 0.326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.323%

Overall 0.32% 5,163/1,613,540 alleles · rare exomes 4,735/1,461,604 · genomes 428/151,936 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.12%	89
Amishnot grpmax-eligible	0.44%	228
European (non-Finnish)grpmax	0.335%	299
Remaining individualsnot grpmax-eligible	0.286%	349
Admixed American	0.257%	389
South Asian	0.122%	820
Ashkenazi Jewishnot grpmax-eligible	0.0608%	1,644
African / African-American	0.0401%	2,496
Middle Eastern	0.033%	3,029

Finnish 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: TBCE
Protein: p.Pro72Ser
Coding: c.214C>T
MANE Select: NM_003193
dbSNP: rs62620041
Type: single nucleotide variant
Location: chr1:235414461 (GRCh38)
Gene constraint: LOEUF 0.868 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.27 · 6 PDB

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

Disease context

hypoparathyroidism-retardation-dysmorphism syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TBCE p.Pro72Leu Uncertain significance ★★ ⚠ same residue
TBCE p.Pro72= Likely benign ★ same residue
TBCE c.100+1G>A Pathogenic/Likely pathogenic ★★ same condition
TBCE p.Arg12Ter Likely pathogenic ★★ same condition
TBCE p.Lys145Ter Pathogenic/Likely pathogenic ★★ same condition
TBCE c.898+6T>C Uncertain significance ★★ same condition
TBCE p.Ala149Gly Uncertain significance ★★ ⚠ same condition
TBCE p.Arg24His 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/tbce-p-pro72ser (accessed [today's date]).

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