Is DEF8 p.Thr171Arg (c.512C>G) pathogenic?

DEF8 p.Thr171Arg (c.512C>G) is classified Uncertain significance in DEF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-01). AlphaMissense: likely benign (0.1274); Very rare (popmax 0.00203%, nfe).

How common is DEF8 p.Thr171Arg (c.512C>G) in the general population?

DEF8 p.Thr171Arg (c.512C>G) is very rare (popmax 0.00203%, nfe) (gnomAD).

What do computational predictors say about DEF8 p.Thr171Arg (c.512C>G)?

AlphaMissense predicts likely benign (score 0.1274) — an in-silico prediction, not a clinical call.

DEF8 p.Thr171Arg

c.512C>G · VCV3271440

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1274 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1274	likely benign
REVEL	0.652	pathogenic-leaning
SaProt	LLR -4.89	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.24 · evaluated, not missing
Pangolin	Δ0.37	loss · gain 0.08 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 12 kb · p 0.019 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM T232R vs ClinVar T171R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00203% European (non-Finnish) · 24/1,180,032 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00164% 24/1,461,598 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: DEF8
Protein: p.Thr171Arg
Coding: c.512C>G
MANE Select: NM_001242818
Type: single nucleotide variant
Location: chr16:89959153 (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-thr171arg (accessed [today's date]).

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