Is DEFA4 p.Pro30Ser (c.88C>T) pathogenic?

DEFA4 p.Pro30Ser (c.88C>T) is classified Uncertain significance in DEFA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-29). AlphaMissense: likely benign (0.069); Very rare (popmax 0.00288%, nfe).

How common is DEFA4 p.Pro30Ser (c.88C>T) in the general population?

DEFA4 p.Pro30Ser (c.88C>T) is very rare (popmax 0.00288%, nfe) (gnomAD).

What do computational predictors say about DEFA4 p.Pro30Ser (c.88C>T)?

AlphaMissense predicts likely benign (score 0.069) — an in-silico prediction, not a clinical call.

DEFA4 p.Pro30Ser

c.88C>T · rs757891881 · VCV2512594

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.069 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.069	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -6.31	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 -6.7	GERP -3
Regional constraint	o/e 1.70	unconstrained · MANE · 876 bp · p 2.8e-15 · regional, not allelic
Overall
CADD	0.316	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 0.00288% European (non-Finnish) · 34/1,179,876 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00217% 35/1,613,612 alleles · very rare exomes 33/1,461,488 · genomes 2/152,124 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00288%	34,702
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: DEFA4
Protein: p.Pro30Ser
Coding: c.88C>T
MANE Select: NM_001925
dbSNP: rs757891881
Type: single nucleotide variant
Location: chr8:6936812 (GRCh38)
Gene constraint: LOEUF 1.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.45 · 3 PDB

Full DEFA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEFA4 p.Ala5Thr Uncertain significance ★ ⚠ same type
DEFA4 p.Arg35His Uncertain significance ★ ⚠ same type
DEFA4 p.Arg74Gln Uncertain significance ★ ⚠ same type
DEFA4 p.Arg78His Uncertain significance ★ ⚠ same type
DEFA4 p.Arg95His Uncertain significance ★ ⚠ same type
DEFA4 p.Asp27Asn Uncertain significance ★ ⚠ same type
DEFA4 p.Gln40Pro Uncertain significance ★ ⚠ same type
DEFA4 p.Ile44Thr 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/defa4-p-pro30ser (accessed [today's date]).

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