Is CSTF2T p.Pro375Ser (c.1123C>T) pathogenic?

CSTF2T p.Pro375Ser (c.1123C>T) is classified Uncertain significance in CSTF2T (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-31). AlphaMissense: likely benign (0.0838); Very rare (popmax 0.00223%, eas).

How common is CSTF2T p.Pro375Ser (c.1123C>T) in the general population?

CSTF2T p.Pro375Ser (c.1123C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CSTF2T p.Pro375Ser (c.1123C>T)?

AlphaMissense predicts likely benign (score 0.0838) — an in-silico prediction, not a clinical call.

CSTF2T p.Pro375Ser

c.1123C>T · rs1435126491 · VCV3078441

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0838 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0838	likely benign
REVEL	0.168	moderately benign-leaning
SaProt	LLR -8.12	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 8.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 810 bp · p 0.42 · regional, not allelic
Overall
CADD	23.8	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 0.00223% East Asian · 1/44,852 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,956 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,852
European (non-Finnish)	0.000254%	393,348

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: CSTF2T
Protein: p.Pro375Ser
Coding: c.1123C>T
MANE Select: NM_015235
dbSNP: rs1435126491
Type: single nucleotide variant
Location: chr10:51698427 (GRCh38)
Gene constraint: LOEUF 0.647 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 60.27
Residue 375: the 'disordered' region

Full CSTF2T gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSTF2T p.Ala158Thr Uncertain significance ★ ⚠ same type
CSTF2T p.Ala417Val Uncertain significance ★ ⚠ same type
CSTF2T p.Ala5Val Uncertain significance ★ ⚠ same type
CSTF2T p.Ala615Val Uncertain significance ★ ⚠ same type
CSTF2T p.Arg302Trp Uncertain significance ★ ⚠ same type
CSTF2T p.Arg373Cys Uncertain significance ★ ⚠ same type
CSTF2T p.Arg373His Uncertain significance ★ ⚠ same type
CSTF2T p.Arg373Ser 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/cstf2t-p-pro375ser (accessed [today's date]).

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