Is CTIF p.Pro280Leu (c.839C>T) pathogenic?

CTIF p.Pro280Leu (c.839C>T) is classified Uncertain significance in CTIF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.0717); Very rare (popmax 0.00466%, nfe).

How common is CTIF p.Pro280Leu (c.839C>T) in the general population?

CTIF p.Pro280Leu (c.839C>T) is very rare (popmax 0.00466%, nfe) (gnomAD).

What do computational predictors say about CTIF p.Pro280Leu (c.839C>T)?

AlphaMissense predicts likely benign (score 0.0717) — an in-silico prediction, not a clinical call.

CTIF p.Pro280Leu

c.839C>T · VCV4235601

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0717 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00466%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0717	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -6.44	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 5.8	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 142 kb · p 0.7 · regional, not allelic
Overall
CADD	18.39	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 0.00466% European (non-Finnish) · 55/1,180,028 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.00353% 57/1,613,870 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00466%	21,455
Admixed American	0.00167%	60,000
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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: CTIF
Protein: p.Pro280Leu
Coding: c.839C>T
MANE Select: NM_014772
Type: single nucleotide variant
Location: chr18:48758173 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 63.13
Residue 280: the 'interaction with ncbp1/cbp80' region; the 'disordered' region

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

Similar variants

CTIF p.Pro280Ser Uncertain significance ★ ⚠ same residue
CTIF c.326+4A>G Benign ★★ same type
CTIF p.Ala63= Benign ★★ same type
CTIF p.Ile277= Benign ★★ same type
CTIF c.1071+5C>T Uncertain significance ★ same type
CTIF p.Ala181Thr Uncertain significance ★ ⚠ same type
CTIF p.Ala271Val Uncertain significance ★ ⚠ same type
CTIF p.Ala304Thr 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/ctif-p-pro280leu (accessed [today's date]).

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