Is DFFB p.Thr177Met (c.530C>T) pathogenic?

DFFB p.Thr177Met (c.530C>T) is classified Uncertain significance in DFFB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). AlphaMissense: likely benign (0.0636); Ultra-rare (popmax 0.0506%, mid).

How common is DFFB p.Thr177Met (c.530C>T) in the general population?

DFFB p.Thr177Met (c.530C>T) is ultra-rare (popmax 0.0506%, mid) (gnomAD).

What do computational predictors say about DFFB p.Thr177Met (c.530C>T)?

AlphaMissense predicts likely benign (score 0.0636) — an in-silico prediction, not a clinical call.

DFFB p.Thr177Met

c.530C>T · VCV3501238

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0636 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0506%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0636	likely benign
REVEL	0.001	strongly benign-leaning
SaProt	LLR -7.66	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 -3.5	GERP -2.8
Regional constraint	o/e 0.90	unconstrained · MANE · 26 kb · p 0.042 · regional, not allelic
Overall
CADD	0.015	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 0.0506% Middle Eastern · 3/5,934 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00733%

Overall 0.0067% 108/1,612,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0506%	1,978
European (non-Finnish)	0.00814%	12,285
African / African-American	0.00801%	12,486
Admixed American	0.00168%	59,648
Remaining individualsnot grpmax-eligible	0.0016%	62,406
South Asian	0.0011%	91,034

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.Thr177Met
Coding: c.530C>T
MANE Select: NM_004402
Type: single nucleotide variant
Location: chr1:3869624 (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.Thr177Ala Uncertain significance ★ ⚠ same residue
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

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-thr177met (accessed [today's date]).

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