Is CDC14B p.Tyr139Cys (c.416A>G) pathogenic?

CDC14B p.Tyr139Cys (c.416A>G) is classified Uncertain significance in CDC14B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-07). AlphaMissense: likely pathogenic (0.8324); Very rare (popmax 0.000257%, nfe).

How common is CDC14B p.Tyr139Cys (c.416A>G) in the general population?

CDC14B p.Tyr139Cys (c.416A>G) is very rare (popmax 0.000257%, nfe) (gnomAD).

What do computational predictors say about CDC14B p.Tyr139Cys (c.416A>G)?

AlphaMissense predicts likely pathogenic (score 0.8324) — an in-silico prediction, not a clinical call.

CDC14B p.Tyr139Cys

c.416A>G · VCV3829708

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8324 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000257%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8324	likely pathogenic
REVEL	0.61	indeterminate
SaProt	LLR -14.88	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 116 kb · p 1.5e-07 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000257% European (non-Finnish) · 3/1,167,116 alleles

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

Overall 0.000188% 3/1,599,646 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: CDC14B
Protein: p.Tyr139Cys
Coding: c.416A>G
MANE Select: NM_033331
Type: single nucleotide variant
Location: chr9:96562697 (GRCh38)
Gene constraint: LOEUF 0.526 · pLI 0.96 (gnomAD)
Structure: AlphaFold pLDDT 81.04 · 3 PDB
Residue 139: an α-helix; the 'a' region

Full CDC14B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDC14B p.Ala13Thr Uncertain significance ★ ⚠ same type
CDC14B p.Ala13Val Uncertain significance ★ ⚠ same type
CDC14B p.Ala14Ser Uncertain significance ★ ⚠ same type
CDC14B p.Ala286Val Uncertain significance ★ ⚠ same type
CDC14B p.Ala388Val Uncertain significance ★ ⚠ same type
CDC14B p.Ala87Thr Uncertain significance ★ ⚠ same type
CDC14B p.Ala95Val Uncertain significance ★ ⚠ same type
CDC14B p.Arg266Lys 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/cdc14b-p-tyr139cys (accessed [today's date]).

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