Is CTIF p.Arg249His (c.746G>A) pathogenic?

CTIF p.Arg249His (c.746G>A) is classified Uncertain significance in CTIF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-16). AlphaMissense: ambiguous (0.3806); Very rare (popmax 0.00534%, afr).

How common is CTIF p.Arg249His (c.746G>A) in the general population?

CTIF p.Arg249His (c.746G>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about CTIF p.Arg249His (c.746G>A)?

AlphaMissense predicts ambiguous (score 0.3806) — an in-silico prediction, not a clinical call.

CTIF p.Arg249His

c.746G>A · VCV3837138

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3806 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Computational evidence

Protein change
AlphaMissense	0.3806	ambiguous
REVEL	0.336	indeterminate
SaProt	LLR -6.63	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 142 kb · p 0.7 · regional, not allelic
Overall
CADD	32.0	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 0.00534% African / African-American · 4/74,866 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000744% 12/1,613,896 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,716
East Asian	0.00446%	22,438
South Asian	0.0022%	45,536
European (non-Finnish)	0.000339%	295,003

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.Arg249His
Coding: c.746G>A
MANE Select: NM_014772
Type: single nucleotide variant
Location: chr18:48758080 (GRCh38)
Gene constraint: LOEUF 0.487 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 63.13
Residue 249: 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.Arg249Cys 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-arg249his (accessed [today's date]).

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