Is TM4SF20 p.Pro153Ser (c.457C>T) pathogenic?

TM4SF20 p.Pro153Ser (c.457C>T) is classified Uncertain significance in TM4SF20 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-09). AlphaMissense: likely benign (0.0621); Absent from gnomAD v4.1; Associated with TM4SF20-related disorder.

What condition is associated with TM4SF20 p.Pro153Ser (c.457C>T)?

TM4SF20 p.Pro153Ser (c.457C>T) is associated with TM4SF20-related disorder (ClinVar).

How common is TM4SF20 p.Pro153Ser (c.457C>T) in the general population?

TM4SF20 p.Pro153Ser (c.457C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TM4SF20 p.Pro153Ser (c.457C>T)?

AlphaMissense predicts likely benign (score 0.0621) — an in-silico prediction, not a clinical call.

TM4SF20 p.Pro153Ser

c.457C>T · rs2076377271 · VCV2635521

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0621 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TM4SF20-related disorder

Computational evidence

Protein change
AlphaMissense	0.0621	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -6.22	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 -4.3	GERP -4.2
Regional constraint	o/e 1.05	unconstrained · MANE · 16 kb · p 0.41 · regional, not allelic
Overall
CADD	0.003	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TM4SF20
Protein: p.Pro153Ser
Coding: c.457C>T
MANE Select: NM_024795
dbSNP: rs2076377271
Type: single nucleotide variant
Location: chr2:227363957 (GRCh38)
Gene constraint: LOEUF 1.228 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.10

Full TM4SF20 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TM4SF20-related disorder

Similar variants

TM4SF20 p.Leu197Phe Uncertain significance ★ ⚠ same condition
TM4SF20 c.250-2A>G Uncertain significance ★★ same type
TM4SF20 p.Arg75Ser Uncertain significance ★★ ⚠ same type
TM4SF20 p.Ile93Thr Uncertain significance ★★ ⚠ same type
TM4SF20 p.Ser91Gly Uncertain significance ★★ ⚠ same type
TM4SF20 p.Trp170Ter Uncertain significance ★★ same type
TM4SF20 p.Val221Ile Uncertain significance ★★ ⚠ same type
TM4SF20 c.250-13T>C Likely benign ★★ 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/tm4sf20-p-pro153ser (accessed [today's date]).

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