Is PPFIBP1 p.Gly726Val (c.2177G>T) pathogenic?

PPFIBP1 p.Gly726Val (c.2177G>T) is classified Uncertain significance in PPFIBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-14). AlphaMissense: likely pathogenic (0.9984); Absent from gnomAD v4.1; Associated with microcephaly.

What condition is associated with PPFIBP1 p.Gly726Val (c.2177G>T)?

PPFIBP1 p.Gly726Val (c.2177G>T) is associated with microcephaly (ClinVar).

How common is PPFIBP1 p.Gly726Val (c.2177G>T) in the general population?

PPFIBP1 p.Gly726Val (c.2177G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PPFIBP1 p.Gly726Val (c.2177G>T)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

PPFIBP1 p.Gly726Val

c.2177G>T · rs2140392469 · VCV1679120

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcephaly

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic · top 1% in PPFIBP1
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -16.04	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 59 kb · p 0.001 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM G732V vs ClinVar G726V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PPFIBP1
Protein: p.Gly726Val
Coding: c.2177G>T
MANE Select: NM_003622
dbSNP: rs2140392469
Type: single nucleotide variant
Location: chr12:27682633 (GRCh38)
Gene constraint: LOEUF 0.911 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.83
Residue 732 UniProt numbering: the sam 2 domain; a UniProt-annotated variant site (in nedsmba); a UniProt-annotated variant site (in nedsmba; uncertain significance)

Full PPFIBP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PPFIBP1 c.1146+1G>A Pathogenic ★ same condition
PPFIBP1 p.Arg135Ter Pathogenic ★ same condition
PPFIBP1 p.Arg805Ter Pathogenic ★ same condition
PPFIBP1 p.Arg877Ter Pathogenic ★ same condition
PPFIBP1 p.Gln434Ter Pathogenic ★ same condition
PPFIBP1 p.Gln490Ter Pathogenic ★ same condition
PPFIBP1 p.Ala473fs Pathogenic ★ same condition
PPFIBP1 p.Glu456fs Pathogenic ★ same condition

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/ppfibp1-p-gly726val (accessed [today's date]).

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