Is DFFA p.Leu140Phe (c.418C>T) pathogenic?

DFFA p.Leu140Phe (c.418C>T) is classified Uncertain significance in DFFA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: likely benign (0.1844); Ultra-rare (popmax 0.0326%, nfe).

How common is DFFA p.Leu140Phe (c.418C>T) in the general population?

DFFA p.Leu140Phe (c.418C>T) is ultra-rare (popmax 0.0326%, nfe) (gnomAD).

What do computational predictors say about DFFA p.Leu140Phe (c.418C>T)?

AlphaMissense predicts likely benign (score 0.1844) — an in-silico prediction, not a clinical call.

DFFA p.Leu140Phe

c.418C>T · rs143293907 · VCV2368301

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1844 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0326%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1844	likely benign
REVEL	0.269	benign-leaning
SaProt	LLR -6.66	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 7.5	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 11 kb · p 0.55 · regional, not allelic
Overall
CADD	23.8	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 0.0326% European (non-Finnish) · 385/1,180,044 alleles

Filtering AF 0.0299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0289%

Overall 0.0248% 400/1,614,006 alleles · ultra-rare exomes 390/1,461,886 · genomes 10/152,120 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0326%	3,065
Remaining individualsnot grpmax-eligible	0.0128%	7,810
African / African-American	0.00801%	12,482
Finnishnot grpmax-eligible	0.00156%	64,042

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.Leu140Phe
Coding: c.418C>T
MANE Select: NM_004401
dbSNP: rs143293907
Type: single nucleotide variant
Location: chr1:10467213 (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.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-leu140phe (accessed [today's date]).

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