Is DFFA p.Thr282Met (c.845C>T) pathogenic?

DFFA p.Thr282Met (c.845C>T) is classified Uncertain significance in DFFA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-06). AlphaMissense: likely benign (0.1247); Very rare (popmax 0.00768%, sas).

How common is DFFA p.Thr282Met (c.845C>T) in the general population?

DFFA p.Thr282Met (c.845C>T) is very rare (popmax 0.00768%, sas) (gnomAD).

What do computational predictors say about DFFA p.Thr282Met (c.845C>T)?

AlphaMissense predicts likely benign (score 0.1247) — an in-silico prediction, not a clinical call.

DFFA p.Thr282Met

c.845C>T · rs375656224 · VCV3081810

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1247 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00768%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1247	likely benign
REVEL	0.337	indeterminate
SaProt	LLR -8.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 11 kb · p 0.55 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00768% South Asian · 7/91,088 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.00204% 33/1,614,118 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00768%	13,013
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.004%	24,980
Admixed American	0.00333%	30,006
Finnishnot grpmax-eligible	0.00156%	64,044
European (non-Finnish)	0.00136%	73,753

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.Thr282Met
Coding: c.845C>T
MANE Select: NM_004401
dbSNP: rs375656224
Type: single nucleotide variant
Location: chr1:10461641 (GRCh38)
Gene constraint: LOEUF 0.784 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.25 · 3 PDB
Residue 282: an α-helix

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.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

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-thr282met (accessed [today's date]).

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