Is DFFA p.Arg296Cys (c.886C>T) pathogenic?

DFFA p.Arg296Cys (c.886C>T) is classified Likely benign in DFFA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2017-09-29). AlphaMissense: ambiguous (0.3638); Rare (popmax 0.261%, nfe).

How common is DFFA p.Arg296Cys (c.886C>T) in the general population?

DFFA p.Arg296Cys (c.886C>T) is rare (popmax 0.261%, nfe) (gnomAD).

What do computational predictors say about DFFA p.Arg296Cys (c.886C>T)?

AlphaMissense predicts ambiguous (score 0.3638) — an in-silico prediction, not a clinical call.

DFFA p.Arg296Cys

c.886C>T · rs137950953 · VCV771301

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3638 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.261%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3638	ambiguous
REVEL	0.356	indeterminate
SaProt	LLR -13.59	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 11 kb · p 0.55 · regional, not allelic
Overall
CADD	25.2	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 0.261% European (non-Finnish) · 3,080/1,180,032 alleles

Filtering AF 0.253% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.25%

Overall 0.218% 3,524/1,614,216 alleles · rare exomes 3,333/1,461,890 · genomes 191/152,326 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.261%	383
Remaining individualsnot grpmax-eligible	0.259%	386
Admixed American	0.252%	398
East Asian	0.0691%	1,448
African / African-American	0.0613%	1,632
Finnishnot grpmax-eligible	0.0609%	1,642
Middle Eastern	0.033%	3,031
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,401
South Asian	0.00988%	10,121

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: DFFA
Protein: p.Arg296Cys
Coding: c.886C>T
MANE Select: NM_004401
dbSNP: rs137950953
Type: single nucleotide variant
Location: chr1:10461600 (GRCh38)
Gene constraint: LOEUF 0.784 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.25 · 3 PDB
Residue 296: an α-helix

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

Similar variants

DFFA p.Cys165Arg Benign ★★ same type
DFFA p.Thr300= Benign ★★ same type
DFFA p.Ala236Val Uncertain significance ★ ⚠ same type
DFFA p.Ala250Pro Uncertain significance ★ ⚠ same type
DFFA p.Ala250Ser Uncertain significance ★ ⚠ same type
DFFA p.Ala294Thr Uncertain significance ★ ⚠ same type
DFFA p.Ala51Pro Uncertain significance ★ ⚠ same type
DFFA p.Ala7Val 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/dffa-p-arg296cys (accessed [today's date]).

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