Is DEF8 p.Arg272His (c.815G>A) pathogenic?

DEF8 p.Arg272His (c.815G>A) is classified Uncertain significance in DEF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely pathogenic (0.5696); Very rare (popmax 0.00445%, eas).

How common is DEF8 p.Arg272His (c.815G>A) in the general population?

DEF8 p.Arg272His (c.815G>A) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about DEF8 p.Arg272His (c.815G>A)?

AlphaMissense predicts likely pathogenic (score 0.5696) — an in-silico prediction, not a clinical call.

DEF8 p.Arg272His

c.815G>A · VCV3839257

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5696 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5696	likely pathogenic
REVEL	0.367	indeterminate
SaProt	LLR -10.66	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.3	GERP 0.65, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 12 kb · p 0.019 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R333H vs ClinVar R272H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,898 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000434% 7/1,613,860 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,449
South Asian	0.0022%	45,547
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000169%	589,998

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: DEF8
Protein: p.Arg272His
Coding: c.815G>A
MANE Select: NM_001242818
Type: single nucleotide variant
Location: chr16:89962019 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.04

Full DEF8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEF8 p.Gln29Glu Benign ★★ same type
DEF8 p.Glu122= Benign ★★ same type
DEF8 p.Pro318= Benign ★★ same type
DEF8 p.Val356Met Likely benign ★★ ⚠ same type
DEF8 c.-11+101C>T Uncertain significance ★ ⚠ same type
DEF8 c.-11+104C>T Uncertain significance ★ ⚠ same type
DEF8 c.-11+10G>T Uncertain significance ★ ⚠ same type
DEF8 c.-11+113C>A 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/def8-p-arg272his (accessed [today's date]).

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