Is DDIT4L p.Pro25Ser (c.73C>T) pathogenic?

DDIT4L p.Pro25Ser (c.73C>T) is classified Uncertain significance in DDIT4L (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-15). AlphaMissense: likely benign (0.0745); Rare (popmax 0.379%, mid).

How common is DDIT4L p.Pro25Ser (c.73C>T) in the general population?

DDIT4L p.Pro25Ser (c.73C>T) is rare (popmax 0.379%, mid) (gnomAD).

What do computational predictors say about DDIT4L p.Pro25Ser (c.73C>T)?

AlphaMissense predicts likely benign (score 0.0745) — an in-silico prediction, not a clinical call.

DDIT4L p.Pro25Ser

c.73C>T · rs201322046 · VCV2226124

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0745 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.379%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0745	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -5.03	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 1.4	GERP -2.6, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 2,303 bp · p 0.49 · regional, not allelic
Overall
CADD	12.76	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 0.379% Middle Eastern · 23/6,062 alleles

Filtering AF 0.259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.22%

Overall 0.0192% 310/1,614,036 alleles · rare exomes 285/1,461,778 · genomes 25/152,258 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.379%	264
Ashkenazi Jewishnot grpmax-eligible	0.328%	305
African / African-American	0.0853%	1,172
Remaining individualsnot grpmax-eligible	0.0704%	1,421
Admixed American	0.045%	2,222
South Asian	0.00769%	13,010
European (non-Finnish)	0.00407%	24,583

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: DDIT4L
Protein: p.Pro25Ser
Coding: c.73C>T
MANE Select: NM_145244
dbSNP: rs201322046
Type: single nucleotide variant
Location: chr4:100189911 (GRCh38)
Gene constraint: LOEUF 1.266 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.03

Full DDIT4L gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DDIT4L p.Ala13Thr Uncertain significance ★ ⚠ same type
DDIT4L p.Ala89Thr Uncertain significance ★ ⚠ same type
DDIT4L p.Arg104Gly Uncertain significance ★ ⚠ same type
DDIT4L p.Arg159Pro Uncertain significance ★ ⚠ same type
DDIT4L p.Asn116Asp Uncertain significance ★ ⚠ same type
DDIT4L p.Asp122Val Uncertain significance ★ ⚠ same type
DDIT4L p.Cys118Arg Uncertain significance ★ same type
DDIT4L p.Gln142Leu 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/ddit4l-p-pro25ser (accessed [today's date]).

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