Is DFFB p.Asp138Glu (c.414C>G) pathogenic?

DFFB p.Asp138Glu (c.414C>G) is classified Uncertain significance in DFFB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-08). AlphaMissense: likely pathogenic (0.9547); Very rare (popmax 0.00351%, amr).

How common is DFFB p.Asp138Glu (c.414C>G) in the general population?

DFFB p.Asp138Glu (c.414C>G) is very rare (popmax 0.00351%, amr) (gnomAD).

What do computational predictors say about DFFB p.Asp138Glu (c.414C>G)?

AlphaMissense predicts likely pathogenic (score 0.9547) — an in-silico prediction, not a clinical call.

DFFB p.Asp138Glu

c.414C>G · VCV4659674

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9547 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00351%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9547	likely pathogenic
REVEL	0.314	indeterminate
SaProt	LLR -7.78	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.3	GERP -2.8, phastCons 0.99
Regional constraint	o/e 0.90	unconstrained · MANE · 26 kb · p 0.042 · regional, not allelic
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00351% Admixed American · 2/56,930 alleles

Filtering AF 0.000583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000218%

Overall 0.000353% 5/1,417,034 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00351%	28,465
Remaining individualsnot grpmax-eligible	0.00166%	60,340
European (non-Finnish)	0.000173%	577,214

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: DFFB
Protein: p.Asp138Glu
Coding: c.414C>G
MANE Select: NM_004402
Type: single nucleotide variant
Location: chr1:3865984 (GRCh38)
Gene constraint: LOEUF 1.143 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.60 · 1 PDB

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

Similar variants

DFFB p.Ala103Thr Uncertain significance ★ ⚠ same type
DFFB p.Ala12Gly Uncertain significance ★ ⚠ same type
DFFB p.Ala131Val Uncertain significance ★ ⚠ same type
DFFB p.Ala132Pro Uncertain significance ★ ⚠ same type
DFFB p.Ala211Thr Uncertain significance ★ ⚠ same type
DFFB p.Arg115Lys Uncertain significance ★ ⚠ same type
DFFB p.Arg165Gln Uncertain significance ★ ⚠ same type
DFFB p.Arg169Lys 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/dffb-p-asp138glu (accessed [today's date]).

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