Is CSTF2 p.Pro257Ser (c.769C>T) pathogenic?

CSTF2 p.Pro257Ser (c.769C>T) is classified Uncertain significance in CSTF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely benign (0.0685); Very rare (popmax 0.00235%, nfe).

How common is CSTF2 p.Pro257Ser (c.769C>T) in the general population?

CSTF2 p.Pro257Ser (c.769C>T) is very rare (popmax 0.00235%, nfe) (gnomAD).

What do computational predictors say about CSTF2 p.Pro257Ser (c.769C>T)?

AlphaMissense predicts likely benign (score 0.0685) — an in-silico prediction, not a clinical call.

CSTF2 p.Pro257Ser

c.769C>T · VCV4235363

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00235%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0685	likely benign
REVEL	0.089	moderately benign-leaning
SaProt	LLR -7.18	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 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 13 kb · p 4.2e-08 · regional, not allelic
Overall
CADD	23.4	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 0.00235% European (non-Finnish) · 21/894,515 alleles

Filtering AF 0.00151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00128%

Overall 0.00174% 21/1,210,260 alleles · very rare exomes 21/1,096,728 · genomes 0/113,532 · 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: CSTF2
Protein: p.Pro257Ser
Coding: c.769C>T
MANE Select: NM_001325
Type: single nucleotide variant
Location: chrX:100826700 (GRCh38)
Structure: AlphaFold pLDDT 60.94 · 4 PDB

Full CSTF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSTF2 p.Pro380= Benign ★★ same type
CSTF2 c.1031+3A>C Uncertain significance ★ same type
CSTF2 p.Ala108Val Uncertain significance ★ ⚠ same type
CSTF2 p.Ala242Val Uncertain significance ★ ⚠ same type
CSTF2 p.Ala263Thr Uncertain significance ★ ⚠ same type
CSTF2 p.Ala427Val Uncertain significance ★ ⚠ same type
CSTF2 p.Arg294Gln Uncertain significance ★ ⚠ same type
CSTF2 p.Arg330Gln 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/cstf2-p-pro257ser (accessed [today's date]).

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