Is DFFA p.Cys165Arg (c.493T>C) pathogenic?

DFFA p.Cys165Arg (c.493T>C) is classified Benign in DFFA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-03-02). AlphaMissense: likely benign (0.0704); Low-frequency (popmax 2.56%, afr).

How common is DFFA p.Cys165Arg (c.493T>C) in the general population?

DFFA p.Cys165Arg (c.493T>C) is low-frequency (popmax 2.56%, afr) (gnomAD).

What do computational predictors say about DFFA p.Cys165Arg (c.493T>C)?

AlphaMissense predicts likely benign (score 0.0704) — an in-silico prediction, not a clinical call.

DFFA p.Cys165Arg

c.493T>C · rs78046004 · VCV777880

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0704 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.56%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0704	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -4.52	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 -0.03	GERP -3.2
Regional constraint	o/e 0.97	unconstrained · MANE · 11 kb · p 0.55 · regional, not allelic
Overall
CADD	5.789	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 2.56% African / African-American · 1,921/75,058 alleles

Filtering AF 2.46% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.43%

Overall 0.243% 3,926/1,614,202 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.56%	39
Ashkenazi Jewishnot grpmax-eligible	2.15%	47
Middle Eastern	2.05%	49
Remaining individualsnot grpmax-eligible	0.486%	206
Admixed American	0.298%	335
European (non-Finnish)	0.0608%	1,646
South Asian	0.0494%	2,024

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.Cys165Arg
Coding: c.493T>C
MANE Select: NM_004401
dbSNP: rs78046004
Type: single nucleotide variant
Location: chr1:10463569 (GRCh38)
Gene constraint: LOEUF 0.784 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.25 · 3 PDB

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

Similar variants

DFFA p.Arg296Cys Likely 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-cys165arg (accessed [today's date]).

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