Is CD70 p.Ser146Ile (c.437G>T) pathogenic?

CD70 p.Ser146Ile (c.437G>T) is classified Uncertain significance in CD70 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-13). AlphaMissense: ambiguous (0.4097); Ultra-rare (popmax 0.0607%, nfe).

How common is CD70 p.Ser146Ile (c.437G>T) in the general population?

CD70 p.Ser146Ile (c.437G>T) is ultra-rare (popmax 0.0607%, nfe) (gnomAD).

What do computational predictors say about CD70 p.Ser146Ile (c.437G>T)?

AlphaMissense predicts ambiguous (score 0.4097) — an in-silico prediction, not a clinical call.

CD70 p.Ser146Ile

c.437G>T · VCV4446396

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4097 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0607%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4097	ambiguous
REVEL	0.358	indeterminate
SaProt	LLR -12.44	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -2.8
Regional constraint	o/e 0.91	unconstrained · MANE · 4,979 bp · p 0.14 · regional, not allelic
Overall
CADD	4.008	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 0.0607% European (non-Finnish) · 716/1,180,040 alleles

Filtering AF 0.0569% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0555%

Overall 0.0477% 770/1,614,138 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0607%	1,648
Remaining individualsnot grpmax-eligible	0.0336%	2,977
Admixed American	0.0283%	3,531
Finnishnot grpmax-eligible	0.0125%	7,999
African / African-American	0.00799%	12,508
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
South Asian	0.0011%	91,076

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: CD70
Protein: p.Ser146Ile
Coding: c.437G>T
MANE Select: NM_001252
Type: single nucleotide variant
Location: chr19:6586165 (GRCh38)
Gene constraint: LOEUF 1.251 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.52 · 1 PDB
Residue 146: the thd domain; a β-strand; a disulfide bond

Full CD70 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD70 p.Leu23Phe Uncertain significance ★★ ⚠ same type
CD70 p.Ser9Leu Uncertain significance ★★ ⚠ same type
CD70 p.Thr118Met Uncertain significance ★★ ⚠ same type
CD70 p.Thr119Met Uncertain significance ★★ ⚠ same type
CD70 p.Val130Met Uncertain significance ★★ ⚠ same type
CD70 p.Cys115= Benign ★★ same type
CD70 p.Gly16= Likely benign ★★ same type
CD70 p.Ser141= Likely benign ★★ 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/cd70-p-ser146ile (accessed [today's date]).

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