Is TBCB p.Pro174Ala (c.520C>G) pathogenic?

TBCB p.Pro174Ala (c.520C>G) is classified Uncertain significance in TBCB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-14). AlphaMissense: likely benign (0.0585); Very rare (popmax 0.00209%, nfe).

How common is TBCB p.Pro174Ala (c.520C>G) in the general population?

TBCB p.Pro174Ala (c.520C>G) is very rare (popmax 0.00209%, nfe) (gnomAD).

What do computational predictors say about TBCB p.Pro174Ala (c.520C>G)?

AlphaMissense predicts likely benign (score 0.0585) — an in-silico prediction, not a clinical call.

TBCB p.Pro174Ala

c.520C>G · rs1425374917 · VCV3174747

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0585 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00209%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0585	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -7.67	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 0.34	GERP -1.5
Regional constraint	o/e 1.00	unconstrained · MANE · 10 kb · p 0.93 · regional, not allelic
Overall
CADD	13.25	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00209% European (non-Finnish) · 24/1,150,726 alleles

Filtering AF 0.00141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00119%

Overall 0.00154% 24/1,554,980 alleles · very rare exomes 23/1,402,786 · genomes 1/152,194 · 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: TBCB
Protein: p.Pro174Ala
Coding: c.520C>G
MANE Select: NM_001281
dbSNP: rs1425374917
Type: single nucleotide variant
Location: chr19:36121691 (GRCh38)
Gene constraint: LOEUF 1.073 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.55

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

Similar variants

TBCB p.Tyr197Asn Uncertain significance ★★ ⚠ same type
TBCB p.Ala218Gly Uncertain significance ★ ⚠ same type
TBCB p.Arg103Gly Uncertain significance ★ ⚠ same type
TBCB p.Arg103Pro Uncertain significance ★ ⚠ same type
TBCB p.Arg138Gln Uncertain significance ★ ⚠ same type
TBCB p.Arg148His Uncertain significance ★ ⚠ same type
TBCB p.Arg196Cys Uncertain significance ★ ⚠ same type
TBCB p.Arg212Cys 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/tbcb-p-pro174ala (accessed [today's date]).

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