Is TCF20 p.Pro1620Ser (c.4858C>T) pathogenic?

TCF20 p.Pro1620Ser (c.4858C>T) is classified Uncertain significance in TCF20 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-20). AlphaMissense: likely benign (0.0986); Ultra-rare (popmax 0.0165%, mid); Associated with developmental delay with variable intellectual impairment and behavioral abnormalities.

How common is TCF20 p.Pro1620Ser (c.4858C>T) in the general population?

TCF20 p.Pro1620Ser (c.4858C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about TCF20 p.Pro1620Ser (c.4858C>T)?

AlphaMissense predicts likely benign (score 0.0986) — an in-silico prediction, not a clinical call.

TCF20 p.Pro1620Ser

Q: What condition is associated with TCF20 p.Pro1620Ser (c.4858C>T)?

TCF20 p.Pro1620Ser (c.4858C>T) is associated with developmental delay with variable intellectual impairment and behavioral abnormalities (ClinVar).

c.4858C>T · rs2518203592 · VCV2437014

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0986 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental delay with variable intellectual impairment and behavioral abnormalities

Computational evidence

Protein change
AlphaMissense	0.0986	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -6.14	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 1.4, phastCons 1
Overall
CADD	19.81	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 6.19e-05% 1/1,614,256 alleles · ultra-rare exomes 1/1,461,894 · genomes 0/152,362 · 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: TCF20
Protein: p.Pro1620Ser
Coding: c.4858C>T
MANE Select: NM_001378418
dbSNP: rs2518203592
Type: single nucleotide variant
Location: chr22:42210448 (GRCh38)
Gene constraint: LOEUF 0.05 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 39.03
Residue 1620: a UniProt-annotated variant site (in ddviba)

Full TCF20 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental delay with variable intellectual impairment and behavioral abnormalities — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TCF20 p.Arg1907Ter Pathogenic ★★ same condition
TCF20 p.Arg742Ter Pathogenic ★★ same condition
TCF20 p.Gln1082Ter Pathogenic/Likely pathogenic ★★ same condition
TCF20 p.Gln471Ter Pathogenic ★★ same condition
TCF20 p.Gln754Ter Pathogenic ★★ same condition
TCF20 p.Trp1861Ter Pathogenic/Likely pathogenic ★★ same condition
TCF20 c.*44+8G>A Uncertain significance ★★ same condition
TCF20 p.Ala1681Val 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/tcf20-p-pro1620ser (accessed [today's date]).

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