Is TCF3 p.Pro29Arg (c.86C>G) pathogenic?

TCF3 p.Pro29Arg (c.86C>G) is classified Conflicting classifications of pathogenicity in TCF3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-22). AlphaMissense: likely pathogenic (0.7816); Ultra-rare (popmax 0.0501%, mid).

How common is TCF3 p.Pro29Arg (c.86C>G) in the general population?

TCF3 p.Pro29Arg (c.86C>G) is ultra-rare (popmax 0.0501%, mid) (gnomAD).

What do computational predictors say about TCF3 p.Pro29Arg (c.86C>G)?

AlphaMissense predicts likely pathogenic (score 0.7816) — an in-silico prediction, not a clinical call.

TCF3 p.Pro29Arg

c.86C>G · rs780251865 · VCV1450832

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7816 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0501%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7816	likely pathogenic
REVEL	0.439	indeterminate
SaProt	LLR -10.55	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 39 kb · p 2.6e-06 · regional, not allelic
Overall
CADD	26.3	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 0.0501% Middle Eastern · 3/5,988 alleles

Filtering AF 0.0168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0159%

Overall 0.0174% 269/1,550,250 alleles · ultra-rare exomes 242/1,397,974 · genomes 27/152,276 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.877%	114
Middle Easterngrpmax	0.0501%	1,996
Remaining individualsnot grpmax-eligible	0.0333%	3,003
South Asian	0.0238%	4,202
European (non-Finnish)	0.0188%	5,309
Admixed American	0.00392%	25,491

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: TCF3
Protein: p.Pro29Arg
Coding: c.86C>G
MANE Select: NM_003200
dbSNP: rs780251865
Type: single nucleotide variant
Location: chr19:1646414 (GRCh38)
Gene constraint: LOEUF 1.239 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 52.42 · 5 PDB

Full TCF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TCF3 p.Arg321Ter Pathogenic ★★ same type
TCF3 p.Glu555Lys Pathogenic ★★ same type
TCF3 c.1327-3C>A Uncertain significance ★★ same type
TCF3 c.652+5A>G Uncertain significance ★★ same type
TCF3 c.955+3A>G Uncertain significance ★★ same type
TCF3 c.955+6G>A Uncertain significance ★★ same type
TCF3 p.Ala109Ser Uncertain significance ★★ ⚠ same type
TCF3 p.Ala115Thr 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/tcf3-p-pro29arg (accessed [today's date]).

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