Is CSTF3 p.Ala59Val (c.176C>T) pathogenic?

CSTF3 p.Ala59Val (c.176C>T) is classified Uncertain significance in CSTF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-23). AlphaMissense: likely benign (0.1028); Very rare (popmax 0.00168%, amr).

How common is CSTF3 p.Ala59Val (c.176C>T) in the general population?

CSTF3 p.Ala59Val (c.176C>T) is very rare (popmax 0.00168%, amr) (gnomAD).

What do computational predictors say about CSTF3 p.Ala59Val (c.176C>T)?

AlphaMissense predicts likely benign (score 0.1028) — an in-silico prediction, not a clinical call.

CSTF3 p.Ala59Val

c.176C>T · rs754549742 · VCV2260792

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1028 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00168%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1028	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -3.50	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 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 55 kb · p 2.4e-14 · regional, not allelic
Overall
CADD	24.0	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 0.00168% Admixed American · 1/59,376 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000496% 8/1,611,548 alleles · very rare exomes 8/1,459,300 · genomes 0/152,248 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00168%	59,376
Remaining individualsnot grpmax-eligible	0.0016%	62,372
European (non-Finnish)	0.000509%	196,554

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: CSTF3
Protein: p.Ala59Val
Coding: c.176C>T
MANE Select: NM_001326
dbSNP: rs754549742
Type: single nucleotide variant
Location: chr11:33141716 (GRCh38)
Gene constraint: LOEUF 0.376 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.85 · 3 PDB

Full CSTF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CSTF3 c.1272+2T>C Uncertain significance ★ same type
CSTF3 p.Arg51Trp Uncertain significance ★ ⚠ same type
CSTF3 p.Arg551Pro Uncertain significance ★ ⚠ same type
CSTF3 p.Arg644Gln Uncertain significance ★ ⚠ same type
CSTF3 p.Asn148Ser Uncertain significance ★ ⚠ same type
CSTF3 p.Asp404Tyr Uncertain significance ★ ⚠ same type
CSTF3 p.Cys628Tyr Uncertain significance ★ ⚠ same type
CSTF3 p.Gln587Glu 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/cstf3-p-ala59val (accessed [today's date]).

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