Is MMS19 p.Ser335Pro (c.1003T>C) pathogenic?

MMS19 p.Ser335Pro (c.1003T>C) is classified Uncertain significance in MMS19 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.2201); Very rare (popmax 0.000171%, nfe).

How common is MMS19 p.Ser335Pro (c.1003T>C) in the general population?

MMS19 p.Ser335Pro (c.1003T>C) is very rare (popmax 0.000171%, nfe) (gnomAD).

What do computational predictors say about MMS19 p.Ser335Pro (c.1003T>C)?

AlphaMissense predicts likely benign (score 0.2201) — an in-silico prediction, not a clinical call.

MMS19 p.Ser335Pro

c.1003T>C · VCV4837040

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2201 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2201	likely benign
REVEL	0.426	indeterminate
SaProt	LLR -7.84	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 2.6, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 11 kb · p 0.0082 · regional, not allelic
Overall
CADD	25.7	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 0.000171% European (non-Finnish) · 2/1,166,608 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000126% 2/1,586,708 alleles · very rare exomes 2/1,434,432 · genomes 0/152,276 · joint denominator

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: MMS19
Protein: p.Ser335Pro
Coding: c.1003T>C
MANE Select: NM_022362
Type: single nucleotide variant
Location: chr10:97469026 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.00

Full MMS19 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MMS19 p.Ala656= Likely benign ★★ same type
MMS19 p.Gln409Pro Benign ★★ same type
MMS19 p.Ala11Val Uncertain significance ★ ⚠ same type
MMS19 p.Ala121Ser Uncertain significance ★ ⚠ same type
MMS19 p.Ala2Val Uncertain significance ★ ⚠ same type
MMS19 p.Ala324Val Uncertain significance ★ ⚠ same type
MMS19 p.Ala383Val Uncertain significance ★ ⚠ same type
MMS19 p.Ala3Val 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/mms19-p-ser335pro (accessed [today's date]).

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