Is TCF12 p.Ser69Phe (c.206C>T) pathogenic?

TCF12 p.Ser69Phe (c.206C>T) is classified Uncertain significance in TCF12 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-29). AlphaMissense: likely benign (0.2065); Very rare (popmax 0.00111%, sas); Associated with Inborn genetic diseases.

What condition is associated with TCF12 p.Ser69Phe (c.206C>T)?

TCF12 p.Ser69Phe (c.206C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TCF12 p.Ser69Phe (c.206C>T) in the general population?

TCF12 p.Ser69Phe (c.206C>T) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about TCF12 p.Ser69Phe (c.206C>T)?

AlphaMissense predicts likely benign (score 0.2065) — an in-silico prediction, not a clinical call.

TCF12 p.Ser69Phe

c.206C>T · rs769528163 · VCV2233962

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2065 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2065	likely benign
REVEL	0.215	benign-leaning
SaProt	LLR -6.18	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 7.7	GERP 4.3, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 353 kb · p 0.079 · regional, not allelic
Overall
CADD	27.7	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 0.00111% South Asian · 1/89,910 alleles

Filtering AF 0.000504% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000368%

Overall 0.000749% 12/1,602,486 alleles · very rare exomes 10/1,450,312 · genomes 2/152,174 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	89,910
European (non-Finnish)	0.000939%	106,468

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: TCF12
Protein: p.Ser69Phe
Coding: c.206C>T
MANE Select: NM_207037
dbSNP: rs769528163
Type: single nucleotide variant
Location: chr15:57063807 (GRCh38)
Gene constraint: LOEUF 0.609 · pLI 0.02 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 51.13 · 2 PDB
Residue 69: the 'disordered' region

Full TCF12 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

TCF12 p.Ala173Thr Uncertain significance ★★ ⚠ same condition
TCF12 p.Asp123Gly Uncertain significance ★★ ⚠ same condition
TCF12 p.Gln4Leu Uncertain significance ★★ ⚠ same condition
TCF12 p.Gln533Glu Uncertain significance ★★ ⚠ same condition
TCF12 p.Met294Val Uncertain significance ★★ ⚠ same condition
TCF12 p.Ser160Pro Uncertain significance ★★ ⚠ same condition
TCF12 p.Thr36Ser Uncertain significance ★★ ⚠ same condition
TCF12 p.Thr687Ala Likely benign ★★ 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/tcf12-p-ser69phe (accessed [today's date]).

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