Is DEXI p.Pro76Ser (c.226C>T) pathogenic?

DEXI p.Pro76Ser (c.226C>T) is classified Uncertain significance in DEXI (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-31). AlphaMissense: likely benign (0.2733); Ultra-rare (popmax 0.0165%, mid).

How common is DEXI p.Pro76Ser (c.226C>T) in the general population?

DEXI p.Pro76Ser (c.226C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about DEXI p.Pro76Ser (c.226C>T)?

AlphaMissense predicts likely benign (score 0.2733) — an in-silico prediction, not a clinical call.

DEXI p.Pro76Ser

c.226C>T · rs146324480 · VCV2368000

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2733 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2733	likely benign
REVEL	0.735	pathogenic-leaning
SaProt	LLR -5.26	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 284 bp · p 0.051 · regional, not allelic
Overall
CADD	31.0	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 0.0165% Middle Eastern · 1/6,046 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00211% 34/1,613,644 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,046
Admixed American	0.00833%	12,000
Remaining individualsnot grpmax-eligible	0.0048%	20,819
African / African-American	0.00267%	37,467
European (non-Finnish)	0.00195%	51,298

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: DEXI
Protein: p.Pro76Ser
Coding: c.226C>T
MANE Select: NM_000246 · reported on NM_014015
dbSNP: rs146324480
Type: single nucleotide variant
Location: chr16:10941780 (GRCh38)

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

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/dexi-p-pro76ser (accessed [today's date]).

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