Is CSTF1 p.Leu197Phe (c.589C>T) pathogenic?

CSTF1 p.Leu197Phe (c.589C>T) is classified Uncertain significance in CSTF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely pathogenic (0.7709); Very rare (popmax 6.84e-05%).

How common is CSTF1 p.Leu197Phe (c.589C>T) in the general population?

CSTF1 p.Leu197Phe (c.589C>T) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about CSTF1 p.Leu197Phe (c.589C>T)?

AlphaMissense predicts likely pathogenic (score 0.7709) — an in-silico prediction, not a clinical call.

CSTF1 p.Leu197Phe

c.589C>T · VCV4235359

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7709	likely pathogenic
REVEL	0.351	indeterminate
SaProt	LLR -9.06	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 6,009 bp · p 1.5e-21 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,816 alleles · very rare

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: CSTF1
Protein: p.Leu197Phe
Coding: c.589C>T
MANE Select: NM_001324
Type: single nucleotide variant
Location: chr20:56397785 (GRCh38)
Gene constraint: LOEUF 0.116 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.65 · 2 PDB
Residue 197: a β-strand

Full CSTF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSTF1 p.Ala68Val Uncertain significance ★ ⚠ same type
CSTF1 p.Arg11His Uncertain significance ★ ⚠ same type
CSTF1 p.Arg221Cys Uncertain significance ★ ⚠ same type
CSTF1 p.Arg339Gln Uncertain significance ★ ⚠ same type
CSTF1 p.Arg401Cys Uncertain significance ★ ⚠ same type
CSTF1 p.Arg71His Uncertain significance ★ ⚠ same type
CSTF1 p.Asn32Ser Uncertain significance ★ ⚠ same type
CSTF1 p.Asn36Ser 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/cstf1-p-leu197phe (accessed [today's date]).

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