Is COL25A1 p.Pro148Ser (c.442C>T) pathogenic?

COL25A1 p.Pro148Ser (c.442C>T) is classified Uncertain significance in COL25A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely benign (0.0803); Ultra-rare (popmax 0.0141%, sas); Associated with Inborn genetic diseases.

What condition is associated with COL25A1 p.Pro148Ser (c.442C>T)?

COL25A1 p.Pro148Ser (c.442C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL25A1 p.Pro148Ser (c.442C>T) in the general population?

COL25A1 p.Pro148Ser (c.442C>T) is ultra-rare (popmax 0.0141%, sas) (gnomAD).

What do computational predictors say about COL25A1 p.Pro148Ser (c.442C>T)?

AlphaMissense predicts likely benign (score 0.0803) — an in-silico prediction, not a clinical call.

COL25A1 p.Pro148Ser

c.442C>T · VCV4232139

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0803 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0141%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0803	likely benign
REVEL	0.385	indeterminate
SaProt	LLR -10.07	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 384 kb · p 0.74 · regional, not allelic
Overall
CADD	21.2	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 0.0141% South Asian · 12/85,214 alleles

Filtering AF 0.00809% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00631%

Overall 0.000826% 13/1,573,424 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0141%	7,101
European (non-Finnish)	8.61e-05%	1,162,093

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: COL25A1
Protein: p.Pro148Ser
Coding: c.442C>T
MANE Select: NM_198721
Type: single nucleotide variant
Location: chr4:108974556 (GRCh38)
Gene constraint: LOEUF 1.034 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.23
Residue 148: the 'disordered' region; the collagen-like 1 domain

Full COL25A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL25A1 p.Pro33Leu Uncertain significance ★★ ⚠ same condition
COL25A1 p.Val44Met Uncertain significance ★★ ⚠ same condition
COL25A1 p.Ala106Thr Uncertain significance ★ ⚠ same condition
COL25A1 p.Ala23Asp Uncertain significance ★ ⚠ same condition
COL25A1 p.Ala23Val Uncertain significance ★ ⚠ same condition
COL25A1 p.Ala290Ser Uncertain significance ★ ⚠ same condition
COL25A1 p.Ala380Val Uncertain significance ★ ⚠ same condition
COL25A1 p.Ala38Val Uncertain significance ★ ⚠ 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/col25a1-p-pro148ser (accessed [today's date]).

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