Is TCF4 p.Pro141Ser (c.421C>T) pathogenic?

TCF4 p.Pro141Ser (c.421C>T) is classified Uncertain significance in TCF4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-07). AlphaMissense: likely benign (0.1163); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with TCF4 p.Pro141Ser (c.421C>T)?

TCF4 p.Pro141Ser (c.421C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TCF4 p.Pro141Ser (c.421C>T) in the general population?

TCF4 p.Pro141Ser (c.421C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TCF4 p.Pro141Ser (c.421C>T)?

AlphaMissense predicts likely benign (score 0.1163) — an in-silico prediction, not a clinical call.

TCF4 p.Pro141Ser

c.421C>T · rs2144786748 · VCV1339619

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1163 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1163	likely benign
REVEL	0.513	indeterminate
SaProt	LLR -5.91	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 96 kb · p 1.2e-10 · regional, not allelic
Overall
CADD	22.4	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 0.0011% South Asian · 1/91,068 alleles

Overall 0.000124% 2/1,613,610 alleles · very rare exomes 2/1,461,330 · genomes 0/152,280 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,470
South Asiangrpmax	0.0011%	91,068

Remaining individuals 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: TCF4
Protein: p.Pro141Ser
Coding: c.421C>T
MANE Select: NM_001083962
dbSNP: rs2144786748
Type: single nucleotide variant
Location: chr18:55350952 (GRCh38)
Gene constraint: LOEUF 0.096 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.08 · 5 PDB
Residue 141: the 'disordered' region

Full TCF4 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

TCF4 p.Pro141= Likely benign ★ same residue
TCF4 p.Gln169Ter Pathogenic ★★ same condition
TCF4 p.Ala444Pro Uncertain significance ★★ ⚠ same condition
TCF4 p.Asp394His Uncertain significance ★★ ⚠ same condition
TCF4 p.Asp492Glu Uncertain significance ★★ ⚠ same condition
TCF4 p.Leu382Ser Uncertain significance ★★ ⚠ same condition
TCF4 p.Lys533Arg Uncertain significance ★★ ⚠ same condition
TCF4 p.Met233Ile 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/tcf4-p-pro141ser (accessed [today's date]).

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