Is CD53 p.Leu142Val (c.424C>G) pathogenic?

CD53 p.Leu142Val (c.424C>G) is classified Uncertain significance in CD53 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-26). AlphaMissense: ambiguous (0.486); Ultra-rare (popmax 0.0107%, afr).

How common is CD53 p.Leu142Val (c.424C>G) in the general population?

CD53 p.Leu142Val (c.424C>G) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about CD53 p.Leu142Val (c.424C>G)?

AlphaMissense predicts ambiguous (score 0.486) — an in-silico prediction, not a clinical call.

CD53 p.Leu142Val

c.424C>G · rs776725210 · VCV2239437

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.486 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.486	ambiguous
REVEL	0.667	pathogenic-leaning
SaProt	LLR -5.62	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.32	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 1.1	GERP -0.4, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 7,783 bp · p 0.0032 · regional, not allelic
Overall
CADD	21.8	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 0.0107% African / African-American · 8/74,778 alleles

Filtering AF 0.00529% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000558% 9/1,611,898 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,347
Remaining individualsnot grpmax-eligible	0.0016%	62,386

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: CD53
Protein: p.Leu142Val
Coding: c.424C>G
MANE Select: NM_000560
dbSNP: rs776725210
Type: single nucleotide variant
Location: chr1:110896653 (GRCh38)
Gene constraint: LOEUF 0.912 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 93.05 · 1 PDB
Residue 142: an α-helix

Full CD53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD53 p.Ala172Val Uncertain significance ★ ⚠ same type
CD53 p.Arg124His Uncertain significance ★ ⚠ same type
CD53 p.Asp120Asn Uncertain significance ★ ⚠ same type
CD53 p.Gly117Asp Uncertain significance ★ ⚠ same type
CD53 p.Gly117Val Uncertain significance ★ ⚠ same type
CD53 p.Gly156Ser Uncertain significance ★ ⚠ same type
CD53 p.His45Arg Uncertain significance ★ ⚠ same type
CD53 p.Ile122Thr 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/cd53-p-leu142val (accessed [today's date]).

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