Is DPY19L4 p.Pro653Ser (c.1957C>T) pathogenic?

DPY19L4 p.Pro653Ser (c.1957C>T) is classified Uncertain significance in DPY19L4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.0729); Ultra-rare (popmax 0.0501%, afr).

How common is DPY19L4 p.Pro653Ser (c.1957C>T) in the general population?

DPY19L4 p.Pro653Ser (c.1957C>T) is ultra-rare (popmax 0.0501%, afr) (gnomAD).

What do computational predictors say about DPY19L4 p.Pro653Ser (c.1957C>T)?

AlphaMissense predicts likely benign (score 0.0729) — an in-silico prediction, not a clinical call.

DPY19L4 p.Pro653Ser

c.1957C>T · rs201689772 · VCV2518043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0729 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0501%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0729	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -5.38	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 4.7	GERP 0.56, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 70 kb · p 0.22 · regional, not allelic
Overall
CADD	14.2	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 0.0501% African / African-American · 35/69,868 alleles

Filtering AF 0.0369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0324%

Overall 0.00265% 40/1,511,564 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0501%	1,996
Admixed American	0.00423%	23,660
Remaining individualsnot grpmax-eligible	0.00347%	28,855
South Asian	0.00136%	73,632

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: DPY19L4
Protein: p.Pro653Ser
Coding: c.1957C>T
MANE Select: NM_181787
dbSNP: rs201689772
Type: single nucleotide variant
Location: chr8:94788002 (GRCh38)
Gene constraint: LOEUF 1.198 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.47

Full DPY19L4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DPY19L4 p.Ala230Val Uncertain significance ★ ⚠ same type
DPY19L4 p.Ala579Val Uncertain significance ★ ⚠ same type
DPY19L4 p.Ala582Val Uncertain significance ★ same type
DPY19L4 p.Arg463Gly Uncertain significance ★ ⚠ same type
DPY19L4 p.Arg516Gln Uncertain significance ★ ⚠ same type
DPY19L4 p.Arg573Gly Uncertain significance ★ ⚠ same type
DPY19L4 p.Arg613Lys Uncertain significance ★ ⚠ same type
DPY19L4 p.Arg76Trp 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/dpy19l4-p-pro653ser (accessed [today's date]).

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