Is PRDM8 p.Ala552Ser (c.1654G>T) pathogenic?

PRDM8 p.Ala552Ser (c.1654G>T) is classified Uncertain significance in PRDM8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-04). AlphaMissense: likely benign (0.0782); Very rare (popmax 0.00177%, amr).

How common is PRDM8 p.Ala552Ser (c.1654G>T) in the general population?

PRDM8 p.Ala552Ser (c.1654G>T) is very rare (popmax 0.00177%, amr) (gnomAD).

What do computational predictors say about PRDM8 p.Ala552Ser (c.1654G>T)?

AlphaMissense predicts likely benign (score 0.0782) — an in-silico prediction, not a clinical call.

PRDM8 p.Ala552Ser

c.1654G>T · VCV3424762

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0782 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00177%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0782	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -7.14	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 2.4	GERP -2.1, phastCons 0.99
Regional constraint	o/e 1.04	unconstrained · MANE · 3,448 bp · p 0.16 · regional, not allelic
Overall
CADD	12.89	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 0.00177% Admixed American · 1/56,454 alleles

Overall 7.06e-05% 1/1,416,240 alleles · very rare

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: PRDM8
Protein: p.Ala552Ser
Coding: c.1654G>T
MANE Select: NM_001099403
Type: single nucleotide variant
Location: chr4:80203116 (GRCh38)
Gene constraint: LOEUF 0.498 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 55.64

Full PRDM8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PRDM8 p.Ala552Gly Uncertain significance ★ ⚠ same residue
PRDM8 p.Ala552Val Uncertain significance ★ ⚠ same residue
PRDM8 p.Ala372Thr Uncertain significance ★★ ⚠ same type
PRDM8 p.Ala416Thr Uncertain significance ★★ ⚠ same type
PRDM8 p.Ala529Val Uncertain significance ★★ ⚠ same type
PRDM8 p.Ala540Ser Uncertain significance ★★ ⚠ same type
PRDM8 p.Ala541Ser Uncertain significance ★★ ⚠ same type
PRDM8 p.Ala546Val 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/prdm8-p-ala552ser (accessed [today's date]).

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