Is CITED4 p.Glu159Lys (c.475G>A) pathogenic?

CITED4 p.Glu159Lys (c.475G>A) is classified Uncertain significance in CITED4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-01). AlphaMissense: likely pathogenic (0.8381); Ultra-rare (popmax 0.0363%, afr).

How common is CITED4 p.Glu159Lys (c.475G>A) in the general population?

CITED4 p.Glu159Lys (c.475G>A) is ultra-rare (popmax 0.0363%, afr) (gnomAD).

What do computational predictors say about CITED4 p.Glu159Lys (c.475G>A)?

AlphaMissense predicts likely pathogenic (score 0.8381) — an in-silico prediction, not a clinical call.

CITED4 p.Glu159Lys

c.475G>A · rs755726577 · VCV2531516

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8381 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0363%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8381	likely pathogenic · top 8% in CITED4
REVEL	0.755	pathogenic-leaning
SaProt	LLR -11.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 2.8, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 551 bp · p 0.00038 · regional, not allelic
Overall
CADD	28.5	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 0.0363% African / African-American · 25/68,842 alleles

Filtering AF 0.0252% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0216%

Overall 0.00173% 26/1,502,816 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0363%	2,754
Admixed American	0.00202%	49,538

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: CITED4
Protein: p.Glu159Lys
Coding: c.475G>A
MANE Select: NM_133467
dbSNP: rs755726577
Type: single nucleotide variant
Location: chr1:40861653 (GRCh38)
Gene constraint: LOEUF 1.958 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.74

Full CITED4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CITED4 p.Ala116Thr Uncertain significance ★ ⚠ same type
CITED4 p.Ala22Gly Uncertain significance ★ ⚠ same type
CITED4 p.Ala28Val Uncertain significance ★ ⚠ same type
CITED4 p.Ala93Glu Uncertain significance ★ ⚠ same type
CITED4 p.Arg155Cys Uncertain significance ★ ⚠ same type
CITED4 p.Arg155Gly Uncertain significance ★ ⚠ same type
CITED4 p.Arg30Gln Uncertain significance ★ ⚠ same type
CITED4 p.Arg30Trp 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/cited4-p-glu159lys (accessed [today's date]).

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