Is CD34 p.Pro166Ser (c.496C>T) pathogenic?

CD34 p.Pro166Ser (c.496C>T) is classified Uncertain significance in CD34 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-30). AlphaMissense: likely benign (0.0716); Very rare (popmax 0.004%, afr).

How common is CD34 p.Pro166Ser (c.496C>T) in the general population?

CD34 p.Pro166Ser (c.496C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about CD34 p.Pro166Ser (c.496C>T)?

AlphaMissense predicts likely benign (score 0.0716) — an in-silico prediction, not a clinical call.

CD34 p.Pro166Ser

c.496C>T · VCV3998237

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0716 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0716	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -6.06	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 -0.49	GERP -2.4
Regional constraint	o/e 0.91	unconstrained · MANE · 23 kb · p 0.059 · regional, not allelic
Overall
CADD	0.126	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 0.004% African / African-American · 3/74,944 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,614,100 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,981
East Asian	0.00223%	44,898

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: CD34
Protein: p.Pro166Ser
Coding: c.496C>T
MANE Select: NM_001025109
Type: single nucleotide variant
Location: chr1:207898993 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.99

Full CD34 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CD34 p.Val127Ile Likely benign ★★ same type
CD34 p.Ala222Val Uncertain significance ★ ⚠ same type
CD34 p.Ala224Asp Uncertain significance ★ ⚠ same type
CD34 p.Ala234Thr Uncertain significance ★ ⚠ same type
CD34 p.Ala349Thr Uncertain significance ★ ⚠ same type
CD34 p.Arg314His Uncertain significance ★ ⚠ same type
CD34 p.Arg315His Uncertain significance ★ ⚠ same type
CD34 p.Arg323Lys 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/cd34-p-pro166ser (accessed [today's date]).

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